@article{SCOPUS_ID:85141004727,

title = {CoDNaS-Q: a database of conformational diversity of the native state of proteins with quaternary structure},

author = {Nahuel Escobedo and Ronaldo Romario Tunque Cahui and Gastón Caruso and Emilio García Ríos and Layla Hirsh and Alexander Miguel Monzon and Gustavo Parisi and Nicolas Palopoli},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85141004727&origin=inward},

doi = {10.1093/bioinformatics/btac627},

year  = {2022},

date = {2022-01-01},

journal = {Bioinformatics},

volume = {38},

number = {21},

pages = {4959-4961},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2022. Published by Oxford University Press. All rights reserved.A collection of conformers that exist in a dynamical equilibrium defines the native state of a protein. The structural differences between them describe their conformational diversity, a defining characteristic of the protein with an essential role in multiple cellular processes. Since most proteins carry out their functions by assembling into complexes, we have developed CoDNaS-Q, the first online resource to explore conformational diversity in homooligomeric proteins. It features a curated collection of redundant protein structures with known quaternary structure. CoDNaS-Q integrates relevant annotations that allow researchers to identify and explore the extent and possible reasons of conformational diversity in homooligomeric protein complexes.},

note = {Cited by: 2; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85122738953,

title = {Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16579 Newborns by Using a Novel Genomic Workflow},

author = {David E. Godler and Ling Ling and Dinusha Gamage and Emma K. Baker and Minh Bui and Michael J. Field and Carolyn Rogers and Merlin G. Butler and Alessandra Murgia and Emanuela Leonardi and Roberta Polli and Charles E. Schwartz and Cindy D. Skinner and Angelica M. Alliende and Lorena Santa Maria and James Pitt and Ronda Greaves and David Francis and Ralph Oertel and Min Wang and Cas Simons and David J. Amor},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85122738953&origin=inward},

doi = {10.1001/jamanetworkopen.2021.41911},

year  = {2022},

date = {2022-01-01},

journal = {JAMA Network Open},

volume = {5},

number = {1},

publisher = {American Medical Association},

abstract = {© 2022 American Medical Association. All rights reserved.Importance: Newborn screening for Angelman syndrome (AS), Prader-Willi syndrome (PWS), and chromosome 15 duplication syndrome (Dup15q) may lead to benefit from early diagnosis and treatment. Objective: To examine the feasibility of newborn screening for these chromosome 15 imprinting disorders at population scale. Design, Setting, and Participants: In this diagnostic study, the validation data set for the first-tier SNRPN test, called methylation-specific quantitative melt analysis (MS-QMA), included 109 PWS, 48 AS, 9 Dup15q, and 1190 population control newborn blood spots (NBS) and peripheral tissue samples from participants recruited from January 2000 to December 2016. The test data set included NBS samples from 16579 infants born in 2011. Infants with an NBS identified as positive for PWS, AS, or Dup15q by the first-tier test were referred for droplet digital polymerase chain reaction, real-time polymerase chain reaction, and low-coverage whole-genome sequencing for confirmatory testing. Data analyses were conducted between February 12, 2015, and August 15, 2020. Results: In the validation data set, the median age for the 77 patients with PWS was 3.00 years (IQR, 0.01-44.50 years); for the 46 patients with AS, 2.76 years (IQR, 0.028 to 49.00 years); and for the 9 patients with Dup15q, 4.00 years (IQR, 1.00 to 28.00 years). Thirty-eight patients (51.4%) in the PWS group, 20 patients (45.5%) in the AS group, and 6 patients (66.7%) in the Dup15q group who had sex reported were male. The validation data set showed MS-QMA sensitivity of 99.0% for PWS, 93.8% for AS, and 77.8% for Dup15q; specificity of 100% for PWS, AS, and Dup15q; positive predictive and negative predictive values of 100% for PWS and AS; and a positive predictive value of 87.5% and negative predictive value of 100% for Dup15q. In the test data set of NBS samples from 16579 infants, 92 had a positive test result using a methylation ratio cut-off of 3 standard deviations from the mean. Of these patients, 2 were confirmed to have PWS; 2, AS; and 1, maternal Dup15q. With the use of more conservative PWS- and AS-specific thresholds for positive calls from the validation data set, 9 positive NBS results were identified by MS-QMA in this cohort. The 2 PWS and 2 AS calls were confirmed by second-tier testing, but the 1 Dup15q case was not confirmed. Together, these results provided prevalence estimates of 1 in 8290 for both AS and PWS and 1 in 16579 for maternal Dup15q, with positive predictive values for first-tier testing at 67.0% for AS, 33.0% for PWS, and 44.0% for combined detection of chromosome 15 imprinting disorders for the validation data set. Conclusions and Relevance: The findings of this diagnostic study suggest that it is feasible to screen for all chromosome 15 imprinting disorders using SNRPN methylation analysis, with 5 individuals identified with these disorders out of 16579 infants screened..},

note = {Cited by: 20; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85122180762,

title = {Molecular Determinants of Selectivity in Disordered Complexes May Shed Light on Specificity in Protein Condensates},

author = {Alexander Miguel Monzon and Damiano Piovesan and Monika Fuxreiter},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85122180762&origin=inward},

doi = {10.3390/biom12010092},

year  = {2022},

date = {2022-01-01},

journal = {Biomolecules},

volume = {12},

number = {1},

publisher = {MDPI},

abstract = {© 2022 by the authors. Licensee MDPI, Basel, Switzerland.Biomolecular condensates challenge the classical concepts of molecular recognition. The variable composition and heterogeneous conformations of liquid‐like protein droplets are bottlenecks for high‐resolution structural studies. To obtain atomistic insights into the organization of these assemblies, here we have characterized the conformational ensembles of specific disordered complexes, including those of droplet‐driving proteins. First, we found that these specific complexes exhibit a high degree of conformational heterogeneity. Second, we found that residues forming contacts at the interface also sample many conformations. Third, we found that different patterns of contacting residues form the specific interface. In addition, we observed a wide range of sequence motifs mediating disordered interactions, including charged, hydrophobic and polar contacts. These results demonstrate that selective recognition can be realized by variable patterns of weakly defined interaction motifs in many different binding configurations. We propose that these principles also play roles in determining the selectivity of biomolecular condensates.},

note = {Cited by: 4; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85134391344,

title = {RING 3.0: fast generation of probabilistic residue interaction networks from structural ensembles},

author = {Damiano Clementel and Alessio Del Conte and Alexander Miguel Monzon and Giorgia F Camagni and Giovanni Minervini and Damiano Piovesan and Silvio C. E Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85134391344&origin=inward},

doi = {10.1093/nar/gkac365},

year  = {2022},

date = {2022-01-01},

journal = {Nucleic Acids Research},

volume = {50},

number = {W1},

pages = {W651-W656},

publisher = {Oxford University Press},

abstract = {© 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.Residue interaction networks (RINs) are used to represent residue contacts in protein structures. Thanks to the advances in network theory, RINs have been proved effective as an alternative to coordinate data in the analysis of complex systems. The RING server calculates high quality and reliable non-covalent molecular interactions based on geometrical parameters. Here, we present the new RING 3.0 version extending the previous functionality in several ways. The underlying software library has been re-engineered to improve speed by an order of magnitude. RING now also supports the mmCIF format and provides typed interactions for the entire PDB chemical component dictionary, including nucleic acids. Moreover, RING now employs probabilistic graphs, where multiple conformations (e.g. NMR or molecular dynamics ensembles) are mapped as weighted edges, opening up new ways to analyze structural data. The web interface has been expanded to include a simultaneous view of the RIN alongside a structure viewer, with both synchronized and clickable. Contact evolution across models (or time) is displayed as a heatmap and can help in the discovery of correlating interaction patterns. The web server, together with an extensive help and tutorial, is available from URL: https://ring.biocomputingup.it/.},

note = {Cited by: 103; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85134406800,

title = {FuzDrop on AlphaFold: visualizing the sequence-dependent propensity of liquid-liquid phase separation and aggregation of proteins},

author = {Andras Hatos and Silvio C. E Tosatto and Michele Vendruscolo and Monika Fuxreiter},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85134406800&origin=inward},

doi = {10.1093/nar/gkac386},

year  = {2022},

date = {2022-01-01},

journal = {Nucleic Acids Research},

volume = {50},

number = {W1},

pages = {W337-W344},

publisher = {Oxford University Press},

abstract = {© 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.Many proteins perform their functions within membraneless organelles, where they form a liquid-like condensed state, also known as droplet state. The FuzDrop method predicts the probability of spontaneous liquid-liquid phase separation of proteins and provides a sequence-based score to identify the regions that promote this process. Furthermore, the FuzDrop method estimates the propensity of conversion of proteins to the amyloid state, and identifies aggregation hot-spots, which can drive the irreversible maturation of the liquid-like droplet state. These predictions can also identify mutations that can induce formation of amyloid aggregates, including those implicated in human diseases. To facilitate the interpretation of the predictions, the droplet-promoting and aggregation-promoting regions can be visualized on protein structures generated by AlphaFold. The FuzDrop server (https://fuzdrop.bio.unipd.it) thus offers insights into the complex behavior of proteins in their condensed states and facilitates the understanding of the functional relationships of proteins.},

note = {Cited by: 66; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85141005149,

title = {Intrinsic protein disorder and conditional folding in AlphaFoldDB},

author = {Damiano Piovesan and Alexander Miguel Monzon and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85141005149&origin=inward},

doi = {10.1002/pro.4466},

year  = {2022},

date = {2022-01-01},

journal = {Protein Science},

volume = {31},

number = {11},

publisher = {John Wiley and Sons Inc},

abstract = {© 2022 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.Intrinsically disordered regions (IDRs) defying the traditional protein structure–function paradigm have been difficult to analyze. The availability of accurate structure predictions on a large scale in AlphaFoldDB offers a fresh perspective on IDR prediction. Here, we establish three baselines for IDR prediction from AlphaFoldDB models based on the recent CAID dataset. Surprisingly, AlphaFoldDB is highly competitive for predicting both IDRs and conditionally folded binding regions, demonstrating the plasticity of the disorder to structure continuum.},

note = {Cited by: 58; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85124603120,

title = {SARS-CoV-2 variants preferentially emerge at intrinsically disordered protein sites helping immune evasion},

author = {Federica Quaglia and Edoardo Salladini and Marco Carraro and Giovanni Minervini and Silvio C. E. Tosatto and Philippe Le Mercier},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85124603120&origin=inward},

doi = {10.1111/febs.16379},

year  = {2022},

date = {2022-01-01},

journal = {FEBS Journal},

volume = {289},

number = {14},

pages = {4240-4250},

publisher = {John Wiley and Sons Inc},

abstract = {© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.The SARS-CoV-2 pandemic is maintained by the emergence of successive variants, highlighting the flexibility of the protein sequences of the virus. We show that experimentally determined intrinsically disordered regions (IDRs) are abundant in the SARS-CoV-2 viral proteins, making up to 28% of disorder content for the S1 subunit of spike and up to 51% for the nucleoprotein, with the vast majority of mutations occurring in the 13 major variants mapped to these IDRs. Strikingly, antigenic sites are enriched in IDRs, in the receptor-binding domain (RBD) and in the N-terminal domain (NTD), suggesting a key role of structural flexibility in the antigenicity of the SARS-CoV-2 protein surface. Mutations occurring in the S1 subunit and nucleoprotein (N) IDRs are critical for immune evasion and antibody escape, suggesting potential additional implications for vaccines and monoclonal therapeutic strategies. Overall, this suggests the presence of variable regions on S1 and N protein surfaces, which confer sequence and antigenic flexibility to the virus without altering its protein functions.},

note = {Cited by: 24; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85131521999,

title = {Molecular Effects of Mutations in Human Genetic Diseases},

author = {Emanuela Leonardi and Castrense Savojardo and Giovanni Minervini},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85131521999&origin=inward},

doi = {10.3390/ijms23126408},

year  = {2022},

date = {2022-01-01},

journal = {International Journal of Molecular Sciences},

volume = {23},

number = {12},

publisher = {MDPI},

note = {Cited by: 0; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85137888553,

title = {Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach},

author = {Cristina Catoni and Cristina Poggiana and Antonella Facchinetti and Jacopo Pigozzo and Luisa Piccin and Vanna Chiarion-Sileni and Antonio Rosato and Giovanni Minervini and Maria Chiara Scaini},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85137888553&origin=inward},

doi = {10.3390/cancers14174153},

year  = {2022},

date = {2022-01-01},

journal = {Cancers},

volume = {14},

number = {17},

publisher = {MDPI},

abstract = {© 2022 by the authors.The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option.},

note = {Cited by: 4; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85123972941,

title = {Databases for intrinsically disordered proteins},

author = {Damiano Piovesan and Alexander Miguel Monzon and Federica Quaglia and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85123972941&origin=inward},

doi = {10.1107/S2059798321012109},

year  = {2022},

date = {2022-01-01},

journal = {Acta Crystallographica Section D: Structural Biology},

volume = {78},

pages = {144-151},

publisher = {International Union of Crystallography},

abstract = {© 2022.Intrinsically disordered regions (IDRs) lacking a fixed three-dimensional protein structure are widespread and play a central role in cell regulation. Only a small fraction of IDRs have been functionally characterized, with heterogeneous experimental evidence that is largely buried in the literature. Predictions of IDRs are still difficult to estimate and are poorly characterized. Here, an overview of the publicly available knowledge about IDRs is reported, including manually curated resources, deposition databases and prediction repositories. The types, scopes and availability of the various resources are analyzed, and their complementarity and overlap are highlighted. The volume of information included and the relevance to the field of structural biology are compared.},

note = {Cited by: 12; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85143181019,

title = {3D-Beacons: Decreasing the gap between protein sequences and structures through a federated network of protein structure data resources},

author = {Mihaly Varadi and Sreenath Nair and Ian Sillitoe and Gerardo Tauriello and Stephen Anyango and Stefan Bienert and Clemente Borges and Mandar Deshpande and Tim Green and Demis Hassabis and Andras Hatos and Tamas Hegedus and Maarten L Hekkelman and Robbie Joosten and John Jumper and Agata Laydon and Dmitry Molodenskiy and Damiano Piovesan and Edoardo Salladini and Steven L Salzberg and Markus J Sommer and Martin Steinegger and Erzsebet Suhajda and Dmitri Svergun and Luiggi Tenorio-Ku and Silvio Tosatto and Kathryn Tunyasuvunakool and Andrew Mark Waterhouse and Augustin Zídek and Torsten Schwede and Christine Orengo and Sameer Velankar},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85143181019&origin=inward},

doi = {10.1093/gigascience/giac118},

year  = {2022},

date = {2022-01-01},

journal = {GigaScience},

volume = {11},

publisher = {Oxford University Press},

abstract = {© 2022 The Author(s). Published by Oxford University Press GigaScience.While scientists can often infer the biological function of proteins from their 3-dimensional quaternary structures, the gap between the number of known protein sequences and their experimentally determined structures keeps increasing. A potential solution to this problem is presented by ever more sophisticated computational protein modeling approaches. While often powerful on their own, most methods have strengths and weaknesses. Therefore, it benefits researchers to examine models from various model providers and perform comparative analysis to identify what models can best address their specific use cases. To make data from a large array of model providers more easily accessible to the broader scientific community, we established 3D-Beacons, a collaborative initiative to create a federated network with unified data access mechanisms. The 3D-Beacons Network allows researchers to collate coordinate files and metadata for experimentally determined and theoretical protein models from state-of-The-Art and specialist model providers and also from the Protein Data Bank.},

note = {Cited by: 15; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85124955220,

title = {Characterization of the pVHL Interactome in Human Testis Using High-Throughput Library Screening},

author = {Antonella Falconieri and Giovanni Minervini and Federica Quaglia and Geppo Sartori and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85124955220&origin=inward},

doi = {10.3390/cancers14041009},

year  = {2022},

date = {2022-01-01},

journal = {Cancers},

volume = {14},

number = {4},

publisher = {MDPI},

abstract = {© 2022 by the authors. Licensee MDPI, Basel, Switzerland.Functional impairment of the von Hippel–Lindau tumor suppressor (pVHL) is causative of a familiar increased risk of developing cancer. As an E3 substrate recognition particle, pVHL marks the hypoxia inducible factor 1α (HIF-1α) for degradation in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. The male mice model carrying VHL gene conditional knockout presents significant abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles. Here we aimed to explore whether pVHL could have a similar role in humans by performing a testis-tissue library screening complemented with in-depth bioinformatics analysis. We identified 55 novel pVHL binding proteins directly involved in spermatogenesis, cell differentiation and reproductive metabolism. In addition, computational investigation of these new interactors identified multiple pVHL-specific binding motifs and demonstrated that somatic mutations described in human cancers reside in these binding regions. Collectively, these findings suggest that, in addition to its role in cancer formation, pVHL may also be pivotal in normal gonadal development in humans.},

note = {Cited by: 1; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85125157608,

title = {DisProt in 2022: Improved quality and accessibility of protein intrinsic disorder annotation},

author = {Federica Quaglia and Bálint Meszáros and Edoardo Salladini and András Hatos and Rita Pancsa and Lucía B. Chemes and Mátyás Pajkos and Tamas Lazar and Samuel Peña-Díaz and Jaime Santos and Veronika Ács and Nazanin Farahi and Erzsebet Fichó and Maria Cristina Aspromonte and Claudio Bassot and Anastasia Chasapi and Norman E. Davey and Radoslav Davidović and Laszlo Dobson and Arne Elofsson and Gábor Erdos and Pascale Gaudet and Michelle Giglio and Juliana Glavina and Javier Iserte and Valentín Iglesias and Zsófia Kálmán and Matteo Lambrughi and Emanuela Leonardi and Sonia Longhi and Sandra Macedo-Ribeiro and Emiliano Maiani and Julia Marchetti and Cristina Marino-Buslje and Attila Meszáros and Alexander Miguel Monzon and Giovanni Minervini and Suvarna Nadendla and Juliet F. Nilsson and Marian Novotný and Christos A. Ouzounis and Nicolás Palopoli and Elena Papaleo and Pedro Jose Barbosa Pereira and Gabriele Pozzati and Vasilis J. Promponas and Jordi Pujols and Alma Carolina Sanchez Rocha and Martin Salas and Luciana Rodriguez Sawicki and Eva Schad and Aditi Shenoy and Tamás Szaniszló and Konstantinos D. Tsirigos and Nevena Veljkovic and Gustavo Parisi and Salvador Ventura and Zsuzsanna Dosztányi and Peter Tompa and Silvio C. E. Tosatto and Damiano Piovesan},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85125157608&origin=inward},

doi = {10.1093/nar/gkab1082},

year  = {2022},

date = {2022-01-01},

journal = {Nucleic Acids Research},

volume = {50},

number = {D1},

pages = {D480-D487},

publisher = {Oxford University Press},

abstract = {© 2022 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure.},

note = {Cited by: 119; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85133241328,

title = {Exploring Manually Curated Annotations of Intrinsically Disordered Proteins with DisProt},

author = {Federica Quaglia and András Hatos and Edoardo Salladini and Damiano Piovesan and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85133241328&origin=inward},

doi = {10.1002/cpz1.484},

year  = {2022},

date = {2022-01-01},

journal = {Current Protocols},

volume = {2},

number = {7},

publisher = {John Wiley and Sons Inc},

abstract = {© 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.DisProt is the major repository of manually curated data for intrinsically disordered proteins collected from the literature. Although lacking a stable three-dimensional structure under physiological conditions, intrinsically disordered proteins carry out a plethora of biological functions, some of them directly arising from their flexible nature. A growing number of scientific studies have been published during the last few decades to shed light on their unstructured state, their binding modes, and their functions. DisProt makes use of a team of expert biocurators to provide up-to-date annotations of intrinsically disordered proteins from the literature, making them available to the scientific community. Here we present a comprehensive description on how to use DisProt in different contexts and provide a detailed explanation of how to explore and interpret manually curated annotations of intrinsically disordered proteins. We describe how to search DisProt annotations, both using the web interface and the API for programmatic access. Finally, we explain how to visualize and interpret a DisProt entry, the SARS-CoV-2 Nucleoprotein, characterized by the presence of unstructured N-terminal and C-terminal regions and a flexible linker. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Performing a search in DisProt. Support Protocol 1: Downloading options. Support Protocol 2: Programmatic access with DisProt REST API. Basic Protocol 2: Exploring the DisProt Ontology page. Basic Protocol 3: Visualizing and interpreting DisProt entries–the SARS-CoV-2 Nucleoprotein use case.},

note = {Cited by: 5; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85098132673,

title = {Intrinsically Disordered Protein Ensembles Shape Evolutionary Rates Revealing Conformational Patterns},

author = {Nicolas Palopoli and Julia Marchetti and Alexander M. Monzon and Diego J. Zea and Silvio C. E. Tosatto and Maria S. Fornasari and Gustavo Parisi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85098132673&origin=inward},

doi = {10.1016/j.jmb.2020.166751},

year  = {2021},

date = {2021-01-01},

journal = {Journal of Molecular Biology},

volume = {433},

number = {3},

publisher = {Academic Press},

abstract = {© 2020 Elsevier LtdIntrinsically disordered proteins (IDPs) lack stable tertiary structure under physiological conditions. The unique composition and complex dynamical behaviour of IDPs make them a challenge for structural biology and molecular evolution studies. Using NMR ensembles, we found that IDPs evolve under a strong site-specific evolutionary rate heterogeneity, mainly originated by different constraints derived from their inter-residue contacts. Evolutionary rate profiles correlate with the experimentally observed conformational diversity of the protein, allowing the description of different conformational patterns possibly related to their structure-function relationships. The correlation between evolutionary rates and contact information improves when structural information is taken not from any individual conformer or the whole ensemble, but from combining a limited number of conformers. Our results suggest that residue contacts in disordered regions constrain evolutionary rates to conserve the dynamic behaviour of the ensemble and that evolutionary rates can be used as a proxy for the conformational diversity of IDPs.},

note = {Cited by: 4; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85121123474,

title = {Intrinsically Disordered Region Modulates Ligand Binding in Glutaredoxin 1 from Trypanosoma Brucei},

author = {Galo. E. Balatti and G. Patricio Barletta and Gustavo Parisi and Silvio. C. E. Tosatto and Massimo Bellanda and Sebastian Fernandez-Alberti},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85121123474&origin=inward},

doi = {10.1021/acs.jpcb.1c07035},

year  = {2021},

date = {2021-01-01},

journal = {Journal of Physical Chemistry B},

volume = {125},

number = {49},

pages = {13366-13375},

publisher = {American Chemical Society},

abstract = {© 2021 American Chemical SocietyGlutaredoxins are small proteins that share a common well-conserved thioredoxin-fold and participate in a wide variety of biological processes. Among them, class II Grx are redox-inactive proteins involved in iron–sulfur (Fe-S) metabolism. In the present work, we report different structural and dynamics aspects of 1CGrx1 from the pathogenic parasite Trypanosoma brucei that differentiate it from other orthologues by the presence of a parasite-specific unstructured N-terminal extension whose role has not been fully elucidated yet. Previous nuclear magnetic resonance (NMR) studies revealed significant differences with respect to the mutant lacking the disordered tail. Herein, we have performed atomistic molecular dynamics simulations that, complementary to NMR studies, confirm the intrinsically disordered nature of the N-terminal extension. Moreover, we confirm the main role of these residues in modulating the conformational dynamics of the glutathione-binding pocket. We observe that the N-terminal extension modifies the ligand cavity stiffening it by specific interactions that ultimately modulate its intrinsic flexibility, which may modify its role in the storage and/or transfer of preformed iron–sulfur clusters. These unique structural and dynamics aspects of Trypanosoma brucei 1CGrx1 differentiate it from other orthologues and could have functional relevance. In this way, our results encourage the study of other similar protein folding families with intrinsically disordered regions whose functional roles are still unrevealed and the screening of potential 1CGrx1 inhibitors as antitrypanosomal drug candidates.},

note = {Cited by: 3},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85105251462,

title = {Characterisation and functional role of a novel C1qDC protein from a colonial ascidian},

author = {Peronato and Minervini and Tabarelli and Ballarin and Franchi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85105251462&origin=inward},

doi = {10.1016/j.dci.2021.104077},

year  = {2021},

date = {2021-01-01},

journal = {Developmental and Comparative Immunology},

volume = {122},

publisher = {Elsevier Ltd},

abstract = {© 2021 Elsevier LtdAs an invertebrate, the compound ascidian Botryllus schlosseri faces nonself only with innate immunity. In this species, we already identified the key components of the lectin and alternative complement activation pathways. In the present work, by mining the transcriptome, we identified a single transcript codifying for a protein, member of the C1q-domain-containing protein family, with a signal peptide followed by two globular C1q (gC1q) domains. It shares a similar domain organisation with C1q/TNF-related proteins 4, the only vertebrate protein family with two gC1q domains. Our gC1q domain-containing protein, called BsC1qDC, is actively transcribed by immunocytes. The transcription is modulated during the Botryllus blastogenetic cycle and is upregulated following the injection of Bacillus clausii cells in the circulation. Furthermore, the injection of bsc1qdc iRNA in the vasculature results in decreased transcription of the gene and a significant impairment of phagocytosis and degranulation, suggesting the involvement of this molecule in immune responses.},

note = {Cited by: 7},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85105906122,

title = {APICURON: A database to credit and acknowledge the work of biocurators},

author = {András Hatos and Federica Quaglia and Damiano Piovesan and Silvio C. E Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85105906122&origin=inward},

doi = {10.1093/database/baab019},

year  = {2021},

date = {2021-01-01},

journal = {Database},

volume = {2021},

publisher = {Oxford University Press},

abstract = {© 2021 The Author(s). Published by Oxford University Press.APICURON is an open and freely accessible resource that tracks and credits the work of biocurators across multiple participating knowledgebases. Biocuration is essential to extract knowledge from research data and make it available in a structured and standardized way to the scientific community. However, processing biological data - mainly from literature - requires a huge effort that is difficult to attribute and quantify. APICURON collects biocuration events from third-party resources and aggregates this information, spotlighting biocurator contributions. APICURON promotes biocurator engagement implementing gamification concepts like badges, medals and leaderboards and at the same time provides a monitoring service for registered resources and for biocurators themselves. APICURON adopts a data model that is flexible enough to represent and track the majority of biocuration activities. Biocurators are identified through their Open Researcher and Contributor ID. The definition of curation events, scoring systems and rules for assigning badges and medals are resource-specific and easily customizable. Registered resources can transfer curation activities on the fly through a secure and robust Application Programming Interface (API). Here, we show how simple and effective it is to connect a resource to APICURON, describing the DisProt database of intrinsically disordered proteins as a use case. We believe APICURON will provide biological knowledgebases with a service to recognize and credit the effort of their biocurators, monitor their activity and promote curator engagement. Database URL: https://apicuron.org},

note = {Cited by: 13; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85105603447,

title = {The f subunit of human ATP synthase is essential for normal mitochondrial morphology and permeability transition},

author = {Chiara Galber and Giovanni Minervini and Giuseppe Cannino and Francesco Boldrin and Valeria Petronilli and Silvio Tosatto and Giovanna Lippe and Valentina Giorgio},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85105603447&origin=inward},

doi = {10.1016/j.celrep.2021.109111},

year  = {2021},

date = {2021-01-01},

journal = {Cell Reports},

volume = {35},

number = {6},

publisher = {Elsevier B.V.},

abstract = {© 2021 The AuthorsThe f subunit is localized at the base of the ATP synthase peripheral stalk. Its function in the human enzyme is poorly characterized. Because full disruption of its ATP5J2 gene with the CRISPR-Cas9 strategy in the HAP1 human model has been shown to cause alterations in the amounts of other ATP synthase subunits, here we investigated the role of the f subunit in HeLa cells by regulating its levels through RNA interference. We confirm the role of the f subunit in ATP synthase dimer stability and observe that its downregulation per se does not alter the amounts of the other enzyme subunits or ATP synthase synthetic/hydrolytic activity. We show that downregulation of the f subunit causes abnormal crista organization and decreases permeability transition pore (PTP) size, whereas its re-expression in f subunit knockdown cells rescues mitochondrial morphology and PTP-dependent swelling.},

note = {Cited by: 30; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85111647557,

title = {Exploring Curated Conformational Ensembles of Intrinsically Disordered Proteins in the Protein Ensemble Database},

author = {Federica Quaglia and Tamas Lazar and András Hatos and Peter Tompa and Damiano Piovesan and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85111647557&origin=inward},

doi = {10.1002/cpz1.192},

year  = {2021},

date = {2021-01-01},

journal = {Current Protocols},

volume = {1},

number = {7},

publisher = {John Wiley and Sons Inc},

abstract = {© 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.The Protein Ensemble Database (PED; https://proteinensemble.org/) is the major repository of conformational ensembles of intrinsically disordered proteins (IDPs). Conformational ensembles of IDPs are primarily provided by their authors or occasionally collected from literature, and are subsequently deposited in PED along with the corresponding structured, manually curated metadata. The modeling of conformational ensembles usually relies on experimental data from small-angle X-ray scattering (SAXS), fluorescence resonance energy transfer (FRET), NMR spectroscopy, and molecular dynamics (MD) simulations, or a combination of these techniques. The growing number of scientific studies based on these data, along with the astounding and swift progress in the field of protein intrinsic disorder, has required a significant update and upgrade of PED, first published in 2014. To this end, the database was entirely renewed in 2020 and now has a dedicated team of biocurators providing manually curated descriptions of the methods and conditions applied to generate the conformational ensembles and for checking consistency of the data. Here, we present a detailed description on how to explore PED with its protein pages and experimental pages, and how to interpret entries of conformational ensembles. We describe how to efficiently search conformational ensembles deposited in PED by means of its web interface and API. We demonstrate how to make sense of the PED protein page and its associated experimental entry pages with reference to the yeast Sic1 use case. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Performing a search in PED. Support Protocol 1: Programmatic access with the PED API. Basic Protocol 2: Interpreting the protein page and the experimental entry page—the Sic1 use case. Support Protocol 2: Downloading options. Support Protocol 3: Understanding the validation report—the Sic1 use case. Basic Protocol 3: Submitting new conformational ensembles to PED. Basic Protocol 4: Providing feedback in PED.},

note = {Cited by: 4; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85099428285,

title = {Pfam: The protein families database in 2021},

author = {Jaina Mistry and Sara Chuguransky and Lowri Williams and Matloob Qureshi and Gustavo A. Salazar and Erik L. L. Sonnhammer and Silvio C. E. Tosatto and Lisanna Paladin and Shriya Raj and Lorna J. Richardson and Robert D. Finn and Alex Bateman},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85099428285&origin=inward},

doi = {10.1093/nar/gkaa913},

year  = {2021},

date = {2021-01-01},

journal = {Nucleic Acids Research},

volume = {49},

number = {D1},

pages = {D412-D419},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.The Pfam database is a widely used resource for classifying protein sequences into families and domains. Since Pfam was last described in this journal, over 350 new families have been added in Pfam 33.1 and numerous improvements have been made to existing entries. To facilitate research on COVID-19, we have revised the Pfam entries that cover the SARS-CoV-2 proteome, and built new entries for regions that were not covered by Pfam. We have reintroduced Pfam-B which provides an automatically generated supplement to Pfam and contains 136 730 novel clusters of sequences that are not yet matched by a Pfam family. The new Pfam-B is based on a clustering by the MMseqs2 software. We have compared all of the regions in the RepeatsDB to those in Pfam and have started to use the results to build and refine Pfam repeat families. Pfam is freely available for browsing and download at http://pfam.xfam.org/.},

note = {Cited by: 3469; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85115828696,

title = {A Novel Splice Variant of Human TGF-β Type II Receptor Encodes a Soluble Protein and Its Fc-Tagged Version Prevents Liver Fibrosis in vivo},

author = {Marcela Soledad Bertolio and Anabela La Colla and Alejandra Carrea and Ana Romo and Gabriela Canziani and Stella Maris Echarte and Sabrina Campisano and German Patricio Barletta and Alexander Miguel Monzon and Tania Melina Rodríguez and Andrea Nancy Chisari and Ricardo Alfredo Dewey},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85115828696&origin=inward},

doi = {10.3389/fcell.2021.690397},

year  = {2021},

date = {2021-01-01},

journal = {Frontiers in Cell and Developmental Biology},

volume = {9},

publisher = {Frontiers Media S.A.},

abstract = {© Copyright © 2021 Bertolio, La Colla, Carrea, Romo, Canziani, Echarte, Campisano, Barletta, Monzon, Rodríguez, Chisari and Dewey.We describe, for the first time, a new splice variant of the human TGF-β type II receptor (TβRII). The new transcript lacks 149 nucleotides, resulting in a frameshift and the emergence of an early stop codon, rendering a truncated mature protein of 57 amino acids. The predicted protein, lacking the transmembrane domain and with a distinctive 13-amino-acid stretch at its C-terminus, was named TβRII-Soluble Endogenous (TβRII-SE). Binding predictions indicate that the novel 13-amino-acid stretch interacts with all three TGF-β cognate ligands and generates a more extensive protein–protein interface than TβRII. TβRII-SE and human IgG1 Fc domain were fused in frame in a lentiviral vector (Lv) for further characterization. With this vector, we transduced 293T cells and purified TβRII-SE/Fc by A/G protein chromatography from conditioned medium. Immunoblotting revealed homogeneous bands of approximately 37 kDa (reduced) and 75 kDa (non-reduced), indicating that TβRII-SE/Fc is secreted as a disulfide-linked homodimer. Moreover, high-affinity binding of TβRII-SE to the three TGF-β isoforms was confirmed by surface plasmon resonance (SPR) analysis. Also, intrahepatic delivery of Lv.TβRII-SE/Fc in a carbon tetrachloride-induced liver fibrosis model revealed amelioration of liver injury and fibrosis. Our results indicate that TβRII-SE is a novel member of the TGF-β signaling pathway with distinctive characteristics. This novel protein offers an alternative for the prevention and treatment of pathologies caused by the overproduction of TGF-β ligands.},

note = {Cited by: 4; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85099428815,

title = {The MemMoRF database for recognizing disordered protein regions interacting with cellular membranes},

author = {Georgina Csizmadia and Gábor Erdős and Hedvig Tordai and Rita Padányi and Silvio Tosatto and Zsuzsanna Dosztányi and Tamás Hegedűs},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85099428815&origin=inward},

doi = {10.1093/nar/gkaa954},

year  = {2021},

date = {2021-01-01},

journal = {Nucleic Acids Research},

volume = {49},

number = {D1},

pages = {D355-D360},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comProtein and lipid membrane interactions play fundamental roles in a large number of cellular processes (e.g. signalling, vesicle trafficking, or viral invasion). A growing number of examples indicate that such interactions can also rely on intrinsically disordered protein regions (IDRs), which can form specific reversible interactions not only with proteins but also with lipids. We named IDRs involved in such membrane lipid-induced disorder-to-order transition as MemMoRFs, in an analogy to IDRs exhibiting disorder-to-order transition upon interaction with protein partners termed Molecular Recognition Features (MoRFs). Currently, both the experimental detection and computational characterization of MemMoRFs are challenging, and information about these regions are scattered in the literature. To facilitate the related investigations we generated a comprehensive database of experimentally validated MemMoRFs based on manual curation of literature and structural data. To characterize the dynamics of MemMoRFs, secondary structure propensity and flexibility calculated from nuclear magnetic resonance chemical shifts were incorporated into the database. These data were supplemented by inclusion of sentences from papers, functional data and disease-related information. The MemMoRF database can be accessed via a user-friendly interface at https://memmorf.hegelab.org, potentially providing a central resource for the characterization of disordered regions in transmembrane and membrane-associated proteins.},

note = {Cited by: 9; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85104988931,

title = {Critical assessment of protein intrinsic disorder prediction},

author = {Marco Necci and Damiano Piovesan and Md Tamjidul Hoque and Ian Walsh and Sumaiya Iqbal and Michele Vendruscolo and Pietro Sormanni and Chen Wang and Daniele Raimondi and Ronesh Sharma and Yaoqi Zhou and Thomas Litfin and Oxana Valerianovna Galzitskaya and Michail Yu. Lobanov and Wim Vranken and Björn Wallner and Claudio Mirabello and Nawar Malhis and Zsuzsanna Dosztányi and Gábor Erdős and Bálint Mészáros and Jianzhao Gao and Kui Wang and Gang Hu and Zhonghua Wu and Alok Sharma and Jack Hanson and Kuldip Paliwal and Isabelle Callebaut and Tristan Bitard-Feildel and Gabriele Orlando and Zhenling Peng and Jinbo Xu and Sheng Wang and David T. Jones and Domenico Cozzetto and Fanchi Meng and Jing Yan and Jörg Gsponer and Jianlin Cheng and Tianqi Wu and Lukasz Kurgan and Vasilis J. Promponas and Stella Tamana and Cristina Marino-Buslje and Elizabeth Martínez-Pérez and Anastasia Chasapi and Christos Ouzounis and A. Keith Dunker and Andrey V. Kajava and Jeremy Y. Leclercq and Burcu Aykac-Fas and Matteo Lambrughi and Emiliano Maiani and Elena Papaleo and Lucia Beatriz Chemes and Lucía Álvarez and Nicolás S. González-Foutel and Valentin Iglesias and Jordi Pujols and Salvador Ventura and Nicolás Palopoli and Guillermo Ignacio Benítez and Gustavo Parisi and Claudio Bassot and Arne Elofsson and Sudha Govindarajan and John Lamb and Marco Salvatore and András Hatos and Alexander Miguel Monzon and Martina Bevilacqua and Ivan Mičetić and Giovanni Minervini and Lisanna Paladin and Federica Quaglia and Emanuela Leonardi and Norman Davey and Tamas Horvath and Orsolya Panna Kovacs and Nikoletta Murvai and Rita Pancsa and Eva Schad and Beata Szabo and Agnes Tantos and Sandra Macedo-Ribeiro and Jose Antonio Manso and Pedro José Barbosa Pereira and Radoslav Davidović and Nevena Veljkovic and Borbála Hajdu-Soltész and Mátyás Pajkos and Tamás Szaniszló and Mainak Guharoy and Tamas Lazar and Mauricio Macossay-Castillo and Peter Tompa and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85104988931&origin=inward},

doi = {10.1038/s41592-021-01117-3},

year  = {2021},

date = {2021-01-01},

journal = {Nature Methods},

volume = {18},

number = {5},

pages = {472-481},

publisher = {Nature Research},

abstract = {© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.Intrinsically disordered proteins, defying the traditional protein structure–function paradigm, are a challenge to study experimentally. Because a large part of our knowledge rests on computational predictions, it is crucial that their accuracy is high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in prediction of intrinsically disordered regions and the subset of residues involved in binding. A total of 43 methods were evaluated on a dataset of 646 proteins from DisProt. The best methods use deep learning techniques and notably outperform physicochemical methods. The top disorder predictor has Fmax = 0.483 on the full dataset and Fmax = 0.792 following filtering out of bona fide structured regions. Disordered binding regions remain hard to predict, with Fmax = 0.231. Interestingly, computing times among methods can vary by up to four orders of magnitude.},

note = {Cited by: 209; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85118615793,

title = {New data on c1qdc from the colonial ascidian botryllus schlosseri},

author = {Peronato and Minervini and Franchi and Loriano Ballarin},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85118615793&origin=inward},

doi = {10.25431/1824-307X/isj.v18i1.130-137},

year  = {2021},

date = {2021-01-01},

journal = {Invertebrate Survival Journal},

volume = {18},

number = {1},

pages = {130-137},

publisher = {Universita degli Studi di Modena e Reggio Emilia},

abstract = {© 2021, Universita degli Studi di Modena e Reggio Emilia. All rights reserved.In the compound ascidian Botryllus schlosseri, we recently identified a novel C1q-domain-containing (C1qDC) protein expressed by circulating immunocytes, called BsC1qDC. It has two globular C1q domains and a signal peptide and can act either as an opsonin and facilitate the phagocytosis of nonself particles or as a cytokine and stimulate the degranulation of cytotoxic cells. In the present work, we used a commercial antibody raised against human CTRP4 (hCTRP4) to provide additional evidences of the involvement of this molecule in immune responses. The antibody was validated in immunoblot analysis and recognizes a band corresponding to the expected molecular weight inferred from the analysis of the amino acid sequence of BsC1qDC. The presence of the antibody in the culture medium in phagocytosis and degranulation assays significantly reduced the two responses. In addition, the relationships between complement C3 activation and bsc1qdc transcription was studied using the injection of C3aR agonist in the colonial vasculature.},

note = {Cited by: 1; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85099149539,

title = {The InterPro protein families and domains database: 20 years on},

author = {Matthias Blum and Hsin-Yu Chang and Sara Chuguransky and Tiago Grego and Swaathi Kandasaamy and Alex Mitchell and Gift Nuka and Typhaine Paysan-Lafosse and Matloob Qureshi and Shriya Raj and Lorna Richardson and Gustavo A. Salazar and Lowri Williams and Peer Bork and Alan Bridge and Julian Gough and Daniel H. Haft and Ivica Letunic and Aron Marchler-Bauer and Huaiyu Mi and Darren A. Natale and Marco Necci and Christine A. Orengo and Arun P. Pandurangan and Catherine Rivoire and Christian J. A. Sigrist and Ian Sillitoe and Narmada Thanki and Paul D. Thomas and Silvio C. E. Tosatto and Cathy H. Wu and Alex Bateman and Robert D. Finn},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85099149539&origin=inward},

doi = {10.1093/nar/gkaa977},

year  = {2021},

date = {2021-01-01},

journal = {Nucleic Acids Research},

volume = {49},

number = {D1},

pages = {D344-D354},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.The InterPro database (https://www.ebi.ac.uk/interpro/) provides an integrative classification of protein sequences into families, and identifies functionally important domains and conserved sites. InterProScan is the underlying software that allows protein and nucleic acid sequences to be searched against InterPro's signatures. Signatures are predictive models which describe protein families, domains or sites, and are provided by multiple databases. InterPro combines signatures representing equivalent families, domains or sites, and provides additional information such as descriptions, literature references and Gene Ontology (GO) terms, to produce a comprehensive resource for protein classification. Founded in 1999, InterPro has become one of the most widely used resources for protein family annotation. Here, we report the status of InterPro (version 81.0) in its 20th year of operation and its associated software, including updates to database content, the release of a new website and REST API, and performance improvements in InterProScan.},

note = {Cited by: 1363; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85116416860,

title = {Identification of rare lrp5 variants in a cohort of males with impaired bone mass},

author = {Maria Santa Rocca and Giovanni Minervini and Andrea Di Nisio and Maurizio Merico and Maria Bueno Marinas and Luca De Toni and Kalliopi Pilichou and Andrea Garolla and Carlo Foresta and Alberto Ferlin},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85116416860&origin=inward},

doi = {10.3390/ijms221910834},

year  = {2021},

date = {2021-01-01},

journal = {International Journal of Molecular Sciences},

volume = {22},

number = {19},

publisher = {MDPI},

abstract = {© 2021 by the authorsLicensee MDPI, Basel, Switzerland.Osteoporosis is the most common bone disease characterized by reduced bone mass and increased bone fragility. Genetic contribution is one of the main causes of primary osteoporosis; therefore, both genders are affected by this skeletal disorder. Nonetheless, osteoporosis in men has received little attention, thus being underestimated and undertreated. The aim of this study was to identify novel genetic variants in a cohort of 128 males with idiopathic low bone mass using a next-generation sequencing (NGS) panel including genes whose mutations could result in reduced bone mineral density (BMD). Genetic analysis detected in eleven patients ten rare heterozygous variants within the LRP5 gene, which were categorized as VUS (variant of uncertain significance), likely pathogenic and benign variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. Protein structural and Bayesian analysis performed on identified LRP5 variants pointed out p.R1036Q and p.R1135C as pathogenic, therefore suggesting the likely association of these two variants with the low bone mass phenotype. In conclusion, this study expands our understanding on the importance of a functional LRP5 protein in bone formation and highlights the necessity to sequence this gene in subjects with idiopathic low BMD.},

note = {Cited by: 4; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85104381200,

title = {A Missense de Novo Variant in the CASK -interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia},

author = {Claudia Ciaccio and Emanuela Leonardi and Roberta Polli and Alessandra Murgia and Stefano D'Arrigo and Elisa Granocchio and Luisa Chiapparini and Chiara Pantaleoni and Silvia Esposito},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85104381200&origin=inward},

doi = {10.1055/s-0041-1725964},

year  = {2021},

date = {2021-01-01},

journal = {Neuropediatrics},

volume = {52},

number = {6},

pages = {484-488},

publisher = {Georg Thieme Verlag},

abstract = {© 2021 Georg Thieme Verlag. All rights reserved.KIRREL3 is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with CASK gene. Alterations of KIRREL3 have been linked to neurodevelopmental disorders, ranging from developmental delay, to autism spectrum disorder, to attention deficit/hyperactivity disorder. The underlying mechanism is not yet fully understood, as it has been hypothesized a fully dominant effect, a risk factor role of KIRREL3 partially penetrating variants, and a recessive inheritance pattern. We report a novel and de novo KIRREL3 mutation in a child affected by severe neurodevelopmental disorder and with brain magnetic resonance imaging evidence of mega cisterna magna and mild cerebellar hypoplasia. This case strengthens the hypothesis that dominant KIRREL3 variants may lead to neurodevelopmental disruption; furthermore, given the strong interaction between KIRREL3 and CASK, we discuss as posterior fossa anomalies may also be part of the phenotype of KIRREL3 -related syndrome.},

note = {Cited by: 4},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85099072292,

title = {Neurocognitive assessment and DNA sequencing expand the phenotype and genotype spectrum of Alström syndrome},

author = {Francesca Dassie and Riccardina Lorusso and Silvia Benavides-Varela and Gabriella Milan and Francesca Favaretto and Edward Callus and Stefano Cagnin and Francesco Reggiani and Giovanni Minervini and Silvio Tosatto and Roberto Vettor and Carlo Semenza and Pietro Maffei},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85099072292&origin=inward},

doi = {10.1002/ajmg.a.62029},

year  = {2021},

date = {2021-01-01},

journal = {American Journal of Medical Genetics, Part A},

volume = {185},

number = {3},

pages = {732-742},

publisher = {John Wiley and Sons Inc},

abstract = {© 2021 Wiley Periodicals LLCAlström syndrome (OMIM#203800) is an ultra-rare autosomal recessive monogenic disease presenting pathogenic variants in ALMS1 (chromosome 2p13). It is characterized by early onset of blindness, hearing loss and systemic comorbidities, with delayed development without cognitive impairment. We aimed to investigate the cognitive functions and describe new pathogenic variants in Alström syndrome patients. Nineteen patients (13 adults, 6 children) underwent a thorough clinical, genetic, laboratory, instrumental, and neurocognitive assessment. Six new pathogenic variants in ALMS1 including the first described in exon 6 were identified. Four patients displayed a “mild phenotype” characterized by slow disease onset or absence of complications, including childhood obesity and association with at least one pathogenic variant in exon 5 or 6. At neurocognitive testing, a significant proportion of patients had deficits in three neurocognitive domains: similarities, phonological memory, and apraxia. In particular, 53% of patients showed difficulties in the auditory working memory test. We found ideomotor and buccofacial apraxia in 74% of patients. “Mild phenotype” patients performed better on auditory working memory and ideomotor apraxia test than “typical phenotype” ones (91.9 + 16.3% vs. 41.7 + 34.5% of correct answers},

note = {Cited by: 5},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85095859724,

title = {PED in 2021: A major update of the protein ensemble database for intrinsically disordered proteins},

author = {Tamas Lazar and Elizabeth Martínez-Pérez and Federica Quaglia and András Hatos and Lucía B. Chemes and Javier A. Iserte and Nicolás A. Méndez and Nicolás A. Garrone and Tadeo E. Saldaño and Julia Marchetti and Ana Julia Velez Rueda and Pau Bernadó and Martin Blackledge and Tiago N. Cordeiro and Eric Fagerberg and Julie D. Forman-Kay and Maria S. Fornasari and Toby J. Gibson and Gregory-Neal W. Gomes and Claudiu C. Gradinaru and Teresa Head-Gordon and Malene Ringkjøbing Jensen and Edward A. Lemke and Sonia Longhi and Cristina Marino-Buslje and Giovanni Minervini and Tanja Mittag and Alexander Miguel Monzon and Rohit V. Pappu and Gustavo Parisi and Sylvie Ricard-Blum and Kiersten M. Ruff and Edoardo Salladini and Marie Skepö and Dmitri Svergun and Sylvain D. Vallet and Mihaly Varadi and Peter Tompa and Silvio C. E. Tosatto and Damiano Piovesan},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85095859724&origin=inward},

doi = {10.1093/nar/gkaa1021},

year  = {2021},

date = {2021-01-01},

journal = {Nucleic Acids Research},

volume = {49},

number = {D1},

pages = {D404-D411},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.The Protein Ensemble Database (PED) (https://proteinensemble.org), which holds structural ensembles of intrinsically disordered proteins (IDPs), has been significantly updated and upgraded since its last release in 2016. The new version, PED 4.0, has been completely redesigned and reimplemented with cutting-edge technology and now holds about six times more data (162 versus 24 entries and 242 versus 60 structural ensembles) and a broader representation of state of the art ensemble generation methods than the previous version. The database has a completely renewed graphical interface with an interactive feature viewer for region-based annotations, and provides a series of descriptors of the qualitative and quantitative properties of the ensembles. High quality of the data is guaranteed by a new submission process, which combines both automatic and manual evaluation steps. A team of biocurators integrate structured metadata describing the ensemble generation methodology, experimental constraints and conditions. A new search engine allows the user to build advanced queries and search all entry fields including cross-references to IDP-related resources such as DisProt, MobiDB, BMRB and SASBDB. We expect that the renewed PED will be useful for researchers interested in the atomic-level understanding of IDP function, and promote the rational, structure-based design of IDP-targeting drugs.},

note = {Cited by: 96; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85111967406,

title = {DOME: recommendations for supervised machine learning validation in biology},

author = {Ian Walsh and Dmytro Fishman and Dario Garcia-Gasulla and Tiina Titma and Gianluca Pollastri and Emidio Capriotti and Rita Casadio and Salvador Capella-Gutierrez and Davide Cirillo and Alessio Del Conte and Alexandros C. Dimopoulos and Victoria Dominguez Del Angel and Joaquin Dopazo and Piero Fariselli and José Maria Fernández and Florian Huber and Anna Kreshuk and Tom Lenaerts and Pier Luigi Martelli and Arcadi Navarro and Pilib Ó Broin and Janet Piñero and Damiano Piovesan and Martin Reczko and Francesco Ronzano and Venkata Satagopam and Castrense Savojardo and Vojtech Spiwok and Marco Antonio Tangaro and Giacomo Tartari and David Salgado and Alfonso Valencia and Federico Zambelli and Jennifer Harrow and Fotis E. Psomopoulos and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85111967406&origin=inward},

doi = {10.1038/s41592-021-01205-4},

year  = {2021},

date = {2021-01-01},

journal = {Nature Methods},

volume = {18},

number = {10},

pages = {1122-1127},

publisher = {Nature Research},

note = {Cited by: 136; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85102363042,

title = {FLIPPER: Predicting and Characterizing Linear Interacting Peptides in the Protein Data Bank},

author = {Alexander Miguel Monzon and Paolo Bonato and Marco Necci and Silvio C. E. Tosatto and Damiano Piovesan},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85102363042&origin=inward},

doi = {10.1016/j.jmb.2021.166900},

year  = {2021},

date = {2021-01-01},

journal = {Journal of Molecular Biology},

volume = {433},

number = {9},

publisher = {Academic Press},

abstract = {© 2021 Elsevier LtdA large fraction of peptides or protein regions are disordered in isolation and fold upon binding. These regions, also called MoRFs, SLiMs or LIPs, are often associated with signaling and regulation processes. However, despite their importance, only a limited number of examples are available in public databases and their automatic detection at the proteome level is problematic. Here we present FLIPPER, an automatic method for the detection of structurally linear sub-regions or peptides that interact with another chain in a protein complex. FLIPPER is a random forest classification that takes the protein structure as input and provides the propensity of each amino acid to be part of a LIP region. Models are built taking into consideration structural features such as intra- and inter-chain contacts, secondary structure, solvent accessibility in both bound and unbound state, structural linearity and chain length. FLIPPER is accurate when evaluated on non-redundant independent datasets, 99% precision and 99% sensitivity on PixelDB-25 and 87% precision and 88% sensitivity on DIBS-25. Finally, we used FLIPPER to process the entire Protein Data Bank and identified different classes of LIPs based on different binding modes and partner molecules. We provide a detailed description of these LIP categories and show that a large fraction of these regions are not detected by disorder predictors. All FLIPPER predictions are integrated in the MobiDB 4.0 database.},

note = {Cited by: 12; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85099427471,

title = {MobiDB: Intrinsically disordered proteins in 2021},

author = {Damiano Piovesan and Marco Necci and Nahuel Escobedo and Alexander Miguel Monzon and András Hatos and Ivan Mičetić and Federica Quaglia and Lisanna Paladin and Pathmanaban Ramasamy and Zsuzsanna Dosztányi and Wim F. Vranken and Norman E. Davey and Gustavo Parisi and Monika Fuxreiter and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85099427471&origin=inward},

doi = {10.1093/nar/gkaa1058},

year  = {2021},

date = {2021-01-01},

journal = {Nucleic Acids Research},

volume = {49},

number = {D1},

pages = {D361-D367},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.The MobiDB database (URL: https://mobidb.org/) provides predictions and annotations for intrinsically disordered proteins. Here, we report recent developments implemented in MobiDB version 4, regarding the database format, with novel types of annotations and an improved update process. The new website includes a re-designed user interface, a more effective search engine and advanced API for programmatic access. The new database schema gives more flexibility for the users, as well as simplifying the maintenance and updates. In addition, the new entry page provides more visualisation tools including customizable feature viewer and graphs of the residue contact maps. MobiDB v4 annotates the binding modes of disordered proteins, whether they undergo disorder-to-order transitions or remain disordered in the bound state. In addition, disordered regions undergoing liquid-liquid phase separation or post-translational modifications are defined. The integrated information is presented in a simplified interface, which enables faster searches and allows large customized datasets to be downloaded in TSV, Fasta or JSON formats. An alternative advanced interface allows users to drill deeper into features of interest. A new statistics page provides information at database and proteome levels. The new MobiDB version presents state-of-the-art knowledge on disordered proteins and improves data accessibility for both computational and experimental users.},

note = {Cited by: 161; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85099429028,

title = {RepeatsDB in 2021: Improved data and extended classification for protein tandem repeat structures},

author = {Lisanna Paladin and Martina Bevilacqua and Sara Errigo and Damiano Piovesan and Ivan Mičetić and Marco Necci and Alexander Miguel Monzon and Maria Laura Fabre and Jose Luis Lopez and Juliet F. Nilsson and Javier Rios and Pablo Lorenzano Menna and Maia Cabrera and Martin Gonzalez Buitron and Mariane Gonçalves Kulik and Sebastian Fernandez-Alberti and Maria Silvina Fornasari and Gustavo Parisi and Antonio Lagares and Layla Hirsh and Miguel A. Andrade-Navarro and Andrey V. Kajava and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85099429028&origin=inward},

doi = {10.1093/nar/gkaa1097},

year  = {2021},

date = {2021-01-01},

journal = {Nucleic Acids Research},

volume = {49},

number = {D1},

pages = {D452-D457},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.The RepeatsDB database (URL: https://repeatsdb.org/) provides annotations and classification for protein tandem repeat structures from the Protein Data Bank (PDB). Protein tandem repeats are ubiquitous in all branches of the tree of life. The accumulation of solved repeat structures provides new possibilities for classification and detection, but also increasing the need for annotation. Here we present RepeatsDB 3.0, which addresses these challenges and presents an extended classification scheme. The major conceptual change compared to the previous version is the hierarchical classification combining top levels based solely on structural similarity (Class > Topology > Fold) with two new levels (Clan > Family) requiring sequence similarity and describing repeat motifs in collaboration with Pfam. Data growth has been addressed with improved mechanisms for browsing the classification hierarchy. A new UniProt-centric view unifies the increasingly frequent annotation of structures from identical or similar sequences. This update of RepeatsDB aligns with our commitment to develop a resource that extracts, organizes and distributes specialized information on tandem repeat protein structures.},

note = {Cited by: 38; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85105148823,

title = {HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia},

author = {Claudio Laquatra and Carlos Sanchez-Martin and Alberto Dinarello and Giuseppe Cannino and Giovanni Minervini and Elisabetta Moroni and Marco Schiavone and Silvio Tosatto and Francesco Argenton and Giorgio Colombo and Paolo Bernardi and Ionica Masgras and Andrea Rasola},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85105148823&origin=inward},

doi = {10.1038/s41419-021-03716-6},

year  = {2021},

date = {2021-01-01},

journal = {Cell Death and Disease},

volume = {12},

number = {5},

publisher = {Springer Nature},

abstract = {© 2021, The Author(s).The mitochondrial paralog of the Hsp90 chaperone family TRAP1 is often induced in tumors, but the mechanisms controlling its expression, as well as its physiological functions remain poorly understood. Here, we find that TRAP1 is highly expressed in the early stages of Zebrafish development, and its ablation delays embryogenesis while increasing mitochondrial respiration of fish larvae. TRAP1 expression is enhanced by hypoxic conditions both in developing embryos and in cancer models of Zebrafish and mammals. The TRAP1 promoter contains evolutionary conserved hypoxic responsive elements, and HIF1α stabilization increases TRAP1 levels. TRAP1 inhibition by selective compounds or by genetic knock-out maintains a high level of respiration in Zebrafish embryos after exposure to hypoxia. Our data identify TRAP1 as a primary regulator of mitochondrial bioenergetics in highly proliferating cells following reduction in oxygen tension and HIF1α stabilization.},

note = {Cited by: 21; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85110173062,

title = {“Protein” no longer means what it used to},

author = {Gustavo Parisi and Nicolas Palopoli and Silvio C. E. Tosatto and María Silvina Fornasari and Peter Tompa},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85110173062&origin=inward},

doi = {10.1016/j.crstbi.2021.06.002},

year  = {2021},

date = {2021-01-01},

journal = {Current Research in Structural Biology},

volume = {3},

pages = {146-152},

publisher = {Elsevier B.V.},

abstract = {© 2021 The AuthorsEvery biologist knows that the word protein describes a group of macromolecules essential to sustain life on Earth. As biologists, we are invariably trained under a protein paradigm established since the early twentieth century. However, in recent years, the term protein unveiled itself as an euphemism to describe the overwhelming heterogeneity of these compounds. Most of our current studies are targeted on carefully selected subsets of proteins, but we tend to think and write about these as representative of the whole population. Here we discuss how seeking for universal definitions and general rules in any arbitrarily segmented study would be misleading about the conclusions. Of course, it is not our purpose to discourage the use of the word protein. Instead, we suggest to embrace the extended universe of proteins to reach a deeper understanding of their full potential, realizing that the term encompasses a group of molecules very heterogeneous in terms of size, shape, chemistry and functions, i.e. the term protein no longer means what it used to.},

note = {Cited by: 3; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85092678821,

title = {Exploring Manually Curated Annotations of Intrinsically Disordered Proteins with DisProt},

author = {Federica Quaglia and András Hatos and Damiano Piovesan and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85092678821&origin=inward},

doi = {10.1002/cpbi.107},

year  = {2020},

date = {2020-01-01},

journal = {Current Protocols in Bioinformatics},

volume = {72},

number = {1},

publisher = {John Wiley and Sons Inc},

abstract = {© 2020 Wiley Periodicals LLCDisProt is the major repository of manually curated data for intrinsically disordered proteins collected from the literature. Although lacking a stable tertiary structure under physiological conditions, intrinsically disordered proteins carry out a plethora of biological functions, some of them directly arising from their flexible nature. A growing number of scientific studies have been published during the last few decades in an effort to shed light on their unstructured state, their binding modes, and their functions. DisProt makes use of a team of expert biocurators to provide up-to-date annotations of intrinsically disordered proteins from the literature, making them available to the scientific community. Here we present a comprehensive description on how to use DisProt in different contexts and provide a detailed explanation of how to explore and interpret manually curated annotations of intrinsically disordered proteins. We describe how to search DisProt annotations, using both the web interface and the API for programmatic access. Finally, we explain how to visualize and interpret a DisProt entry, p53, a widely studied protein characterized by the presence of unstructured N-terminal and C-terminal regions. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Performing a search in DisProt. Support Protocol 1: Downloading options. Support Protocol 2: Programmatic access with DisProt REST API. Basic Protocol 2: Visualizing and interpreting DisProt entries: the p53 use case. Basic Protocol 3: Providing feedback and submitting new intrinsic disorder−related data.},

note = {Cited by: 2; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85079208028,

title = {In silico prediction of blood cholesterol levels from genotype data},

author = {Francesco Reggiani and Marco Carraro and Anna Belligoli and Marta Sanna and Chiara Prà and Francesca Favaretto and Carlo Ferrari and Roberto Vettor and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85079208028&origin=inward},

doi = {10.1371/journal.pone.0227191},

year  = {2020},

date = {2020-01-01},

journal = {PLoS ONE},

volume = {15},

number = {2},

publisher = {Public Library of Scienceplos@plos.org},

abstract = {© 2020 Reggiani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.In this work we present a framework for blood cholesterol levels prediction from genotype data. The predictor is based on an algorithm for cholesterol metabolism simulation available in literature, implemented and optimized by our group in the R language. The main weakness of the former simulation algorithm was the need of experimental data to simulate mutations in genes altering the cholesterol metabolism. This caveat strongly limited the application of the model in the clinical practice. In this work we present how this limitation could be bypassed thanks to an optimization of model parameters based on patient cholesterol levels retrieved from literature. Prediction performance has been assessed taking into consideration several scoring indices currently used for performance evaluation of machine learning methods. Our assessment shows how the optimization phase improved model performance, compared to the original version available in literature.},

note = {Cited by: 3; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85085478685,

title = {Frequency of Usher gene mutations in non-syndromic hearing loss: higher variability of the Usher phenotype},

author = {Federica Cesca and Elisa Bettella and Roberta Polli and Emanuela Leonardi and Maria Cristina Aspromonte and Barbara Sicilian and Franco Stanzial and Francesco Benedicenti and Alberto Sensi and Andrea Ciorba and Stefania Bigoni and Elona Cama and Pietro Scimemi and Rosamaria Santarelli and Alessandra Murgia},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85085478685&origin=inward},

doi = {10.1038/s10038-020-0783-1},

year  = {2020},

date = {2020-01-01},

journal = {Journal of Human Genetics},

volume = {65},

number = {10},

pages = {855-864},

publisher = {Springer Nature},

abstract = {© 2020, The Author(s), under exclusive licence to The Japan Society of Human Genetics.Non-syndromic hearing loss (NSHL) is characterized by a vast genetic heterogeneity; some syndromic forms as Usher syndrome (USH) have onset as isolated deafness and then evolve later in life. We developed an NGS targeted gene-panel containing 59 genes and a customized bioinformatic pipeline for the analysis of DNA samples from clinically highly selected subjects with sensorineural hearing loss, previously resulted negative for GJB2 mutations/GJB6 deletions. Among the 217 tested subjects, 24 (11.1%) were found to carry mutations in genes involved both in NSHL and USH. For 6 out of 24 patients a diagnosis of USH was performed. Eleven subjects out of 24 had hearing loss without vestibular or ocular dysfunction and, due to their young age, it was not possible to establish whether their phenotype could be NSHL or USH. Seven subjects were diagnosed with NSHL, due to their age and phenotype. A total of 41 likely pathogenic/pathogenic mutations were identified, among which 17 novel ones. We report a high frequency of mutations in genes involved both in NSHL and in USH in a cohort of individuals tested for seemingly isolated deafness. Our data also highlight a wider than expected phenotypic variability in the USH phenotype.},

note = {Cited by: 8},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85077666918,

title = {DisProt: Intrinsic protein disorder annotation in 2020},

author = {András Hatos and Borbála Hajdu-Soltész and Alexander M. Monzon and Nicolas Palopoli and Lucía Álvarez and Burcu Aykac-Fas and Claudio Bassot and Guillermo I. Benítez and Martina Bevilacqua and Anastasia Chasapi and Lucia Chemes and Norman E. Davey and Radoslav Davidović and A Keith Dunker and Arne Elofsson and Julien Gobeill and Nicolás S González Foutel and Govindarajan Sudha and Mainak Guharoy and Tamas Horvath and Valentin Iglesias and Andrey V. Kajava and Orsolya P. Kovacs and John Lamb and Matteo Lambrughi and Tamas Lazar and Jeremy Y. Leclercq and Emanuela Leonardi and Sandra MacEdo-Ribeiro and Mauricio MacOssay-Castillo and Emiliano Maiani and José A. Manso and Cristina Marino-Buslje and Elizabeth Martínez-Pérez and Bálint Mészáros and Ivan Mičetić and Giovanni Minervini and Nikoletta Murvai and Marco Necci and Christos A. Ouzounis and Mátyás Pajkos and Lisanna Paladin and Rita Pancsa and Elena Papaleo and Gustavo Parisi and Emilie Pasche and Pedro J. Barbosa Pereira and Vasilis J. Promponas and Jordi Pujols and Federica Quaglia and Patrick Ruch and Marco Salvatore and Eva Schad and Beata Szabo and Tamás Szaniszló and Stella Tamana and Agnes Tantos and Nevena Veljkovic and Salvador Ventura and Wim Vranken and Zsuzsanna Dosztányi and Peter Tompa and Silvio C. E. Tosatto and Damiano Piovesan},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85077666918&origin=inward},

doi = {10.1093/nar/gkz975},

year  = {2020},

date = {2020-01-01},

journal = {Nucleic Acids Research},

volume = {48},

number = {D1},

pages = {D269-D276},

publisher = {Oxford University Press},

abstract = {© 2019 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.The Database of Protein Disorder (DisProt, URL: https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the 'dark' proteome.},

note = {Cited by: 195; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85086855750,

title = {Experimentally determined long intrinsically disordered protein regions are now abundant in the protein data bank},

author = {Alexander Miguel Monzon and Marco Necci and Federica Quaglia and Ian Walsh and Giuseppe Zanotti and Damiano Piovesan and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85086855750&origin=inward},

doi = {10.3390/ijms21124496},

year  = {2020},

date = {2020-01-01},

journal = {International Journal of Molecular Sciences},

volume = {21},

number = {12},

pages = {1-13},

publisher = {MDPI AGPostfachBaselCH-4005rasetti@mdpi.com},

abstract = {© 2020 by the authors. Licensee MDPI, Basel, Switzerland.Intrinsically disordered protein regions are commonly defined from missing electron density in X-ray structures. Experimental evidence for long disorder regions (LDRs) of at least 30 residues was so far limited to manually curated proteins. Here, we describe a comprehensive and large-scale analysis of experimental LDRs for 3133 unique proteins, demonstrating an increasing coverage of intrinsic disorder in the Protein Data Bank (PDB) in the last decade. The results suggest that long missing residue regions are a good quality source to annotate intrinsically disordered regions and perform functional analysis in large data sets. The consensus approach used to define LDRs allows to evaluate context dependent disorder and provide a common definition at the protein level.},

note = {Cited by: 26; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85098481915,

title = {Identification of SETBP1 Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With “Developmental and Epileptic Encephalopathy”},

author = {Emanuela Leonardi and Elisa Bettella and Maria Federica Pelizza and Maria Cristina Aspromonte and Roberta Polli and Clementina Boniver and Stefano Sartori and Donatella Milani and Alessandra Murgia},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85098481915&origin=inward},

doi = {10.3389/fneur.2020.593446},

year  = {2020},

date = {2020-01-01},

journal = {Frontiers in Neurology},

volume = {11},

publisher = {Frontiers Media S.A.},

abstract = {© Copyright © 2020 Leonardi, Bettella, Pelizza, Aspromonte, Polli, Boniver, Sartori, Milani and Murgia.SETBP1 mutations are associated with the Schinzel-Giedion syndrome (SGS), characterized by profound neurodevelopmental delay, typical facial features, and multiple congenital malformations (OMIM 269150). Refractory epilepsy is a common feature of SGS. Loss of function mutations have been typically associated with a distinct and milder phenotype characterized by intellectual disability and expressive speech impairment. Here we report three variants of SETBP1, two novel de novo truncating mutations, identified by NGS analysis of an Intellectual Disability gene panel in 600 subjects with non-specific neurodevelopmental disorders, and one missense identified by a developmental epilepsy gene panel tested in 56 pediatric epileptic cases. The three individuals carrying the identified SETBP1 variants presented mild to severe developmental delay and lacked the cardinal features of classical SGS. One of these subjects, carrying the c.1765C>T (p.Arg589*) mutation, had mild Intellectual Disability with speech delay; the second one carrying the c.2199_2203del (p.Glu734Alafs19*) mutation had generalized epilepsy, responsive to treatment, and moderate Intellectual Disability; the third patient showed a severe cognitive defects and had a history of drug resistant epilepsy with West syndrome evolved into a Lennox-Gastaut syndrome. This latter subject carries the missense c.2572G>A (p.Glu858Lys) variant, which is absent from the control population, reported as de novo in a subject with ASD, and located close to the SETBP1 hot spot for SGS-associated mutations. Our findings contribute to further characterizing the associated phenotypes and suggest inclusion of SETBP1 in the list of prioritized genes for the genetic diagnosis of overlapping phenotypes ranging from non-specific neurodevelopmental disorders to “developmental and epileptic encephalopathy” (DEE).},

note = {Cited by: 16; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85100492379,

title = {MobiDB-lite 3.0: Fast consensus annotation of intrinsic disorder flavors in proteins},

author = {Marco Necci and Damiano Piovesan and Damiano Clementel and Zsuzsanna Dosztányi and Silvio C. E Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85100492379&origin=inward},

doi = {10.1093/bioinformatics/btaa1045},

year  = {2020},

date = {2020-01-01},

journal = {Bioinformatics},

volume = {36},

number = {22-23},

pages = {5533-5534},

publisher = {Oxford University Press},

abstract = {© 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.Motivation: The earlier version of MobiDB-lite is currently used in large-scale proteome annotation platforms to detect intrinsic disorder. However, new theoretical models allow for the classification of intrinsically disordered regions into subtypes from sequence features associated with specific polymeric properties or compositional bias. Results: MobiDB-lite 3.0 maintains its previous speed and performance but also provides a finer classification of disorder by identifying regions with characteristics of polyolyampholytes, positive or negative polyelectrolytes, low-complexity regions or enriched in cysteine, proline or glycine or polar residues. Subregions are abundantly detected in IDRs of the human proteome. The new version of MobiDB-lite represents a new step for the proteome level analysis of protein disorder.},

note = {Cited by: 57; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85099166712,

title = {Expanding the genetic landscape of Rett syndrome to include lysine acetyltransferase 6A (KAT6A)},

author = {Simranpreet Kaur and Nicole J. Van Bergen and Bruria Ben-Zeev and Emanuela Leonardi and Tiong Y. Tan and David Coman and Benjamin Kamien and Susan M. White and Miya St John and Dean Phelan and Kristin Rigbye and Sze Chern Lim and Michelle C. Torres and Melanie Marty and Elena Savva and Teresa Zhao and Sean Massey and Alessandra Murgia and Wendy A. Gold and John Christodoulou},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85099166712&origin=inward},

doi = {10.1016/j.jgg.2020.09.003},

year  = {2020},

date = {2020-01-01},

journal = {Journal of Genetics and Genomics},

volume = {47},

number = {10},

pages = {650-654},

publisher = {Institute of Genetics and Developmental Biology},

note = {Cited by: 2},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85084693969,

title = {The Feature-Viewer: A visualization tool for positional annotations on a sequence},

author = {Lisanna Paladin and Mathieu Schaeffer and Pascale Gaudet and Monique Zahn-Zabal and Pierre-André Michel and Damiano Piovesan and Silvio C. E. Tosatto and Amos Bairoch},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85084693969&origin=inward},

doi = {10.1093/bioinformatics/btaa055},

year  = {2020},

date = {2020-01-01},

journal = {Bioinformatics},

volume = {36},

number = {10},

pages = {3244-3245},

publisher = {Oxford University Press},

abstract = {© 2020 The Author(s). Published by Oxford University Press. All rights reserved.The Feature-Viewer is a lightweight library for the visualization of biological data mapped to a protein or nucleotide sequence. It is designed for ease of use while allowing for a full customization. The library is already used by several biological data resources and allows intuitive visual mapping of a full spectra of sequence features for different usages.},

note = {Cited by: 18; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85082481693,

title = {A novel WAC loss of function mutation in an individual presenting with encephalopathy related to status epilepticus during sleep (ESES)},

author = {Emanuela Leonardi and Mariagrazia Bellini and Maria C. Aspromonte and Roberta Polli and Anna Mercante and Claudia Ciaccio and Elisa Granocchio and Elisa Bettella and Ilaria Donati and Elisa Cainelli and Stefania Boni and Stefano Sartori and Chiara Pantaleoni and Clementina Boniver and Alessandra Murgia},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85082481693&origin=inward},

doi = {10.3390/genes11030344},

year  = {2020},

date = {2020-01-01},

journal = {Genes},

volume = {11},

number = {3},

publisher = {MDPI AGPostfachBaselCH-4005rasetti@mdpi.com},

abstract = {© 2020 by the authors. Licensee MDPI, Basel, Switzerland.WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.},

note = {Cited by: 14; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85093107322,

title = {Chasing coevolutionary signals in intrinsically disordered proteins complexes},

author = {Javier A. Iserte and Tamas Lazar and Silvio C. E. Tosatto and Peter Tompa and Cristina Marino-Buslje},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85093107322&origin=inward},

doi = {10.1038/s41598-020-74791-6},

year  = {2020},

date = {2020-01-01},

journal = {Scientific Reports},

volume = {10},

number = {1},

publisher = {Nature Researchsubscriptions@nature.com},

abstract = {© 2020, The Author(s).Intrinsically disordered proteins/regions (IDPs/IDRs) are crucial components of the cell, they are highly abundant and participate ubiquitously in a wide range of biological functions, such as regulatory processes and cell signaling. Many of their important functions rely on protein interactions, by which they trigger or modulate different pathways. Sequence covariation, a powerful tool for protein contact prediction, has been applied successfully to predict protein structure and to identify protein–protein interactions mostly of globular proteins. IDPs/IDRs also mediate a plethora of protein–protein interactions, highlighting the importance of addressing sequence covariation-based inter-protein contact prediction of this class of proteins. Despite their importance, a systematic approach to analyze the covariation phenomena of intrinsically disordered proteins and their complexes is still missing. Here we carry out a comprehensive critical assessment of coevolution-based contact prediction in IDP/IDR complexes and detail the challenges and possible limitations that emerge from their analysis. We found that the coevolutionary signal is faint in most of the complexes of disordered proteins but positively correlates with the interface size and binding affinity between partners. In addition, we discuss the state-of-art methodology by biological interpretation of the results, formulate evaluation guidelines and suggest future directions of development to the field.},

note = {Cited by: 8; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85092318936,

title = {The role of mitochondrial ATP synthase in cancer},

author = {Chiara Galber and Manuel Jesus Acosta and Giovanni Minervini and Valentina Giorgio},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85092318936&origin=inward},

doi = {10.1515/hsz-2020-0157},

year  = {2020},

date = {2020-01-01},

journal = {Biological Chemistry},

volume = {401},

number = {11},

pages = {1199-1214},

publisher = {De Gruyter Open Ltd},

abstract = {© 2020 De Gruyter. All rights reserved.The mitochondrial ATP synthase is a multi-subunit enzyme complex located in the inner mitochondrial membrane which is essential for oxidative phosphorylation under physiological conditions. In this review, we analyse the enzyme functions involved in cancer progression by dissecting specific conditions in which ATP synthase contributes to cancer development or metastasis. Moreover, we propose the role of ATP synthase in the formation of the permeability transition pore (PTP) as an additional mechanism which controls tumour cell death. We further describe transcriptional and translational modifications of the enzyme subunits and of the inhibitor protein IF1 that may promote adaptations leading to cancer metabolism. Finally, we outline ATP synthase gene mutations and epigenetic modifications associated with cancer development or drug resistance, with the aim of highlighting this enzyme complex as a potential novel target for future anti-cancer therapy.},

note = {Cited by: 35; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85084626047,

title = {Revenant: A database of resurrected proteins},

author = {Matias Sebastian Carletti and Alexander Miguel Monzon and Emilio Garcia-Rios and Guillermo Benitez and Layla Hirsh and Maria Silvina Fornasari and Gustavo Parisi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85084626047&origin=inward},

doi = {10.1093/database/baaa031},

year  = {2020},

date = {2020-01-01},

journal = {Database},

volume = {2020},

publisher = {Oxford University Press},

abstract = {© 2020 The Author(s) 2020. Published by Oxford University Press.Revenant is a database of resurrected proteins coming from extinct organisms. Currently, it contains a manually curated collection of 84 resurrected proteins derived from bibliographic data. Each protein is extensively annotated, including structural, biochemical and biophysical information. Revenant contains a browse capability designed as a timeline from where the different proteins can be accessed. The oldest Revenant entries are between 4200 and 3500 million years ago, while the younger entries are between 8.8 and 6.3 million years ago. These proteins have been resurrected using computational tools called ancestral sequence reconstruction techniques combined with wet-laboratory synthesis and expression. Resurrected proteins are commonly used, with a noticeable increase during the past years, to explore and test different evolutionary hypotheses such as protein stability, to explore the origin of new functions, to get biochemical insights into past metabolisms and to explore specificity and promiscuous behaviour of ancient proteins.},

note = {Cited by: 6; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85086793285,

title = {Exploring Conformational Space with Thermal Fluctuations Obtained by Normal-Mode Analysis},

author = {Tadeo E. Saldanõ and Victor M. Freixas and Silvio C. E. Tosatto and Gustavo Parisi and Sebastian Fernandez-Alberti},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85086793285&origin=inward},

doi = {10.1021/acs.jcim.9b01136},

year  = {2020},

date = {2020-01-01},

journal = {Journal of Chemical Information and Modeling},

volume = {60},

number = {6},

pages = {3068-3080},

publisher = {American Chemical Society},

abstract = {© 2020 American Chemical Society.Proteins in their native states can be represented as ensembles of conformers in dynamical equilibrium. Thermal fluctuations are responsible for transitions between these conformers. Normal-modes analysis (NMA) using elastic network models (ENMs) provides an efficient procedure to explore global dynamics of proteins commonly associated with conformational transitions. In the present work, we present an iterative approach to explore protein conformational spaces by introducing structural distortions according to their equilibrium dynamics at room temperature. The approach can be used either to perform unbiased explorations of conformational space or to explore guided pathways connecting two different conformations, e.g., apo and holo forms. In order to test its performance, four proteins with different magnitudes of structural distortions upon ligand binding have been tested. In all cases, the conformational selection model has been confirmed and the conformational space between apo and holo forms has been encompassed. Different strategies have been tested that impact on the efficiency either to achieve a desired conformational change or to achieve a balanced exploration of the protein conformational multiplicity.},

note = {Cited by: 3},

keywords = {},

pubstate = {published},

tppubtype = {article}

}