PUBLICATIONS

@article{SCOPUS_ID:85069236811,

title = {INGA 2.0: Improving protein function prediction for the dark proteome},

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

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85069236811&origin=inward},

doi = {10.1093/nar/gkz375},

year  = {2019},

date = {2019-01-01},

journal = {Nucleic Acids Research},

volume = {47},

number = {W1},

pages = {W373-W378},

publisher = {Oxford University Press},

abstract = {© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.Our current knowledge of complex biological systems is stored in a computable form through the Gene Ontology (GO) which provides a comprehensive description of genes function. Prediction of GO terms from the sequence remains, however, a challenging task, which is particularly critical for novel genomes. Here we present INGA 2.0, a new version of the INGA software for protein function prediction. INGA exploits homology, domain architecture, interaction networks and information from the 'dark proteome', like transmembrane and intrinsically disordered regions, to generate a consensus prediction. INGA was ranked in the top ten methods on both CAFA2 and CAFA3 blind tests. The new algorithm can process entire genomes in a few hours or even less when additional input files are provided. The new interface provides a better user experience by integrating filters and widgets to explore the graph structure of the predicted terms. The INGA web server, databases and benchmarking are available from URL: https://inga.bio.unipd.it/.},

note = {Cited by: 25; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85070077996,

title = {Characterization of intellectual disability and autism comorbidity through gene panel sequencing},

author = {Maria C. Aspromonte and Mariagrazia Bellini and Alessandra Gasparini and Marco Carraro and Elisa Bettella and Roberta Polli and Federica Cesca and Stefania Bigoni and Stefania Boni and Ombretta Carlet and Susanna Negrin and Isabella Mammi and Donatella Milani and Angela Peron and Stefano Sartori and Irene Toldo and Fiorenza Soli and Licia Turolla and Franco Stanzial and Francesco Benedicenti and Cristina Marino-Buslje and Silvio C. E. Tosatto and Alessandra Murgia and Emanuela Leonardi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85070077996&origin=inward},

doi = {10.1002/humu.23822},

year  = {2019},

date = {2019-01-01},

journal = {Human Mutation},

volume = {40},

number = {9},

pages = {1346-1363},

publisher = {John Wiley and Sons Inc.P.O.Box 18667NewarkNJ 07191-8667},

abstract = {© 2019 Wiley Periodicals, Inc.Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.},

note = {Cited by: 50; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85076296099,

title = {An intrinsically disordered proteins community for ELIXIR [version 1; peer review: 2 approved]},

author = {Norman E. Davey and M. Madan Babu and Martin Blackledge and Alan Bridge and Salvador Capella-Gutierrez and Zsuzsanna Dosztanyi and Rachel Drysdale and Richard J. Edwards and Arne Elofsson and Isabella C. Felli and Toby J. Gibson and Aleksandras Gutmanas and John M. Hancock and Jen Harrow and Desmond Higgins and Cy M. Jeffries and Philippe Le Mercier and Balint Meszaros and Marco Necci and Cedric Notredame and Sandra Orchard and Christos A. Ouzounis and Rita Pancsa and Elena Papaleo and Roberta Pierattelli and Damiano Piovesan and Vasilis J. Promponas and Patrick Ruch and Gabriella Rustici and Pedro Romero and Sirarat Sarntivijai and Gary Saunders and Benjamin Schuler and Malvika Sharan and Denis C. Shields and Joel L. Sussman and Jonathan A. Tedds and Peter Tompa and Michael Turewicz and Jiri Vondrasek and Wim F. Vranken and Bonnie Ann Wallace and Kanin Wichapong and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85076296099&origin=inward},

doi = {10.12688/f1000research.20136.1},

year  = {2019},

date = {2019-01-01},

journal = {F1000Research},

volume = {8},

publisher = {F1000 Research Ltd},

abstract = {© 2019 Davey NE et al.Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) are now recognised as major determinants in cellular regulation. This white paper presents a roadmap for future e-infrastructure developments in the field of IDP research within the ELIXIR framework. The goal of these developments is to drive the creation of high-quality tools and resources to support the identification, analysis and functional characterisation of IDPs. The roadmap is the result of a workshop titled “An intrinsically disordered protein user community proposal for ELIXIR” held at the University of Padua. The workshop, and further consultation with the members of the wider IDP community, identified the key priority areas for the roadmap including the development of standards for data annotation, storage and dissemination; integration of IDP data into the ELIXIR Core Data Resources; and the creation of benchmarking criteria for IDP-related software. Here, we discuss these areas of priority, how they can be implemented in cooperation with the ELIXIR platforms, and their connections to existing ELIXIR Communities and international consortia. The article provides a preliminary blueprint for an IDP Community in ELIXIR and is an appeal to identify and involve new stakeholders.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85058530143,

title = {InterPro in 2019: Improving coverage, classification and access to protein sequence annotations},

author = {Alex L Mitchell and Teresa K Attwood and Patricia C Babbitt and Matthias Blum and Peer Bork and Alan Bridge and Shoshana D Brown and Hsin-Yu Chang and Sara El-Gebali and Matthew I Fraser and Julian Gough and David R Haft and Hongzhan Huang and Ivica Letunic and Rodrigo Lopez and Aurélien Luciani and Fabio Madeira and Aron Marchler-Bauer and Huaiyu Mi and Darren A Natale and Marco Necci and Gift Nuka and Christine Orengo and Arun P Pandurangan and Typhaine Paysan-Lafosse and Sebastien Pesseat and Simon C Potter and Matloob A Qureshi and Neil D Rawlings and Nicole Redaschi and Lorna J Richardson and Catherine Rivoire and Gustavo A Salazar and Amaia Sangrador-Vegas and Christian J A Sigrist and Ian Sillitoe and Granger G Sutton and Narmada Thanki and Paul D Thomas and Silvio C E Tosatto and Siew-Yit Yong and Robert D Finn},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85058530143&origin=inward},

doi = {10.1093/nar/gky1100},

year  = {2019},

date = {2019-01-01},

journal = {Nucleic Acids Research},

volume = {47},

number = {D1},

pages = {D351-D360},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.The InterPro database (http://www.ebi.ac.uk/interpro/) classifies protein sequences into families and predicts the presence of functionally important domains and sites. Here, we report recent developments with InterPro (version 70.0) and its associated software, including an 18% growth in the size of the database in terms on new InterPro entries, updates to content, the inclusion of an additional entry type, refined modelling of discontinuous domains, and the development of a new programmatic interface and website. These developments extend and enrich the information provided by InterPro, and provide greater flexibility in terms of data access. We also show that InterPro's sequence coverage has kept pace with the growth of UniProtKB, and discuss how our evaluation of residue coverage may help guide future curation activities.},

note = {Cited by: 1156; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85075272104,

title = {The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens},

author = {Naihui Zhou and Yuxiang Jiang and Timothy R. Bergquist and Alexandra J. Lee and Balint Z. Kacsoh and Alex W. Crocker and Kimberley A. Lewis and George Georghiou and Huy N. Nguyen and Md Nafiz Hamid and Larry Davis and Tunca Dogan and Volkan Atalay and Ahmet S. Rifaioglu and Alperen Dalklran and Rengul Cetin Atalay and Chengxin Zhang and Rebecca L. Hurto and Peter L. Freddolino and Yang Zhang and Prajwal Bhat and Fran Supek and José M. Fernández and Branislava Gemovic and Vladimir R. Perovic and Radoslav S. Davidović and Neven Sumonja and Nevena Veljkovic and Ehsaneddin Asgari and Mohammad R. K. Mofrad and Giuseppe Profiti and Castrense Savojardo and Pier Luigi Martelli and Rita Casadio and Florian Boecker and Heiko Schoof and Indika Kahanda and Natalie Thurlby and Alice C. McHardy and Alexandre Renaux and Rabie Saidi and Julian Gough and Alex A. Freitas and Magdalena Antczak and Fabio Fabris and Mark N. Wass and Jie Hou and Jianlin Cheng and Zheng Wang and Alfonso E. Romero and Alberto Paccanaro and Haixuan Yang and Tatyana Goldberg and Chenguang Zhao and Liisa Holm and Petri Törönen and Alan J. Medlar and Elaine Zosa and Itamar Borukhov and Ilya Novikov and Angela Wilkins and Olivier Lichtarge and Po-Han Chi and Wei-Cheng Tseng and Michal Linial and Peter W. Rose and Christophe Dessimoz and Vedrana Vidulin and Saso Dzeroski and Ian Sillitoe and Sayoni Das and Jonathan Gill Lees and David T. Jones and Cen Wan and Domenico Cozzetto and Rui Fa and Mateo Torres and Alex Warwick Vesztrocy and Jose Manuel Rodriguez and Michael L. Tress and Marco Frasca and Marco Notaro and Giuliano Grossi and Alessandro Petrini and Matteo Re and Giorgio Valentini and Marco Mesiti and Daniel B. Roche and Jonas Reeb and David W. Ritchie and Sabeur Aridhi and Seyed Ziaeddin Alborzi and Marie-Dominique Devignes and Da Chen Emily Koo and Richard Bonneau and Vladimir Gligorijević and Meet Barot and Hai Fang and Stefano Toppo and Enrico Lavezzo and ...},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85075272104&origin=inward},

doi = {10.1186/s13059-019-1835-8},

year  = {2019},

date = {2019-01-01},

journal = {Genome Biology},

volume = {20},

number = {1},

publisher = {BioMed Central Ltd.info@biomedcentral.com},

abstract = {© 2019 The Author(s).Background: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function. Results: Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-Term memory. Conclusion: We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.},

note = {Cited by: 352; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85059794859,

title = {The Pfam protein families database in 2019},

author = {Sara El-Gebali and Jaina Mistry and Alex Bateman and Sean R. Eddy and Aurélien Luciani and Simon C. Potter and Matloob Qureshi and Lorna J. Richardson and Gustavo A. Salazar and Alfredo Smart and Erik L. L. Sonnhammer and Layla Hirsh and Lisanna Paladin and Damiano Piovesan and Silvio C. E. Tosatto and Robert D. Finn},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85059794859&origin=inward},

doi = {10.1093/nar/gky995},

year  = {2019},

date = {2019-01-01},

journal = {Nucleic Acids Research},

volume = {47},

number = {D1},

pages = {D427-D432},

publisher = {Oxford University Press},

abstract = {© 2018 The Author(s).The last few years have witnessed significant changes in Pfam (https://pfam.xfam.org). The number of families has grown substantially to a total of 17,929 in release 32.0. New additions have been coupled with efforts to improve existing families, including refinement of domain boundaries, their classification into Pfam clans, as well as their functional annotation. We recently began to collaborate with the RepeatsDB resource to improve the definition of tandem repeat families within Pfam. We carried out a significant comparison to the structural classification database, namely the Evolutionary Classification of Protein Domains (ECOD) that led to the creation of 825 new families based on their set of uncharacterized families (EUFs). Furthermore, we also connected Pfam entries to the Sequence Ontology (SO) through mapping of the Pfam type definitions to SO terms. Since Pfam has many community contributors, we recently enabled the linking between authorship of all Pfam entries with the corresponding authors- ORCID identifiers. This effectively permits authors to claim credit for their Pfam curation and link them to their ORCID record.},

note = {Cited by: 3581; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85071323430,

title = {Assessing computational predictions of the phenotypic effect of cystathionine-beta-synthase variants},

author = {Laura Kasak and Constantina Bakolitsa and Zhiqiang Hu and Changhua Yu and Jasper Rine and Dago F. Dimster-Denk and Gaurav Pandey and Greet De Baets and Yana Bromberg and Chen Cao and Emidio Capriotti and Rita Casadio and Joost Van Durme and Manuel Giollo and Rachel Karchin and Panagiotis Katsonis and Emanuela Leonardi and Olivier Lichtarge and Pier Luigi Martelli and David Masica and Sean D. Mooney and Ayodeji Olatubosun and Predrag Radivojac and Frederic Rousseau and Lipika R. Pal and Castrense Savojardo and Joost Schymkowitz and Janita Thusberg and Silvio C. E. Tosatto and Mauno Vihinen and Jouni Väliaho and Susanna Repo and John Moult and Steven E. Brenner and Iddo Friedberg},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85071323430&origin=inward},

doi = {10.1002/humu.23868},

year  = {2019},

date = {2019-01-01},

journal = {Human Mutation},

volume = {40},

number = {9},

pages = {1530-1545},

publisher = {John Wiley and Sons Inc},

abstract = {© 2019 Wiley Periodicals, Inc.Accurate prediction of the impact of genomic variation on phenotype is a major goal of computational biology and an important contributor to personalized medicine. Computational predictions can lead to a better understanding of the mechanisms underlying genetic diseases, including cancer, but their adoption requires thorough and unbiased assessment. Cystathionine-beta-synthase (CBS) is an enzyme that catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine, and in which variations are associated with human hyperhomocysteinemia and homocystinuria. We have created a computational challenge under the CAGI framework to evaluate how well different methods can predict the phenotypic effect(s) of CBS single amino acid substitutions using a blinded experimental data set. CAGI participants were asked to predict yeast growth based on the identity of the mutations. The performance of the methods was evaluated using several metrics. The CBS challenge highlighted the difficulty of predicting the phenotype of an ex vivo system in a model organism when classification models were trained on human disease data. We also discuss the variations in difficulty of prediction for known benign and deleterious variants, as well as identify methodological and experimental constraints with lessons to be learned for future challenges.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85072180336,

title = {Insights into the molecular features of the von Hippel–Lindau-like protein},

author = {Giovanni Minervini and Federica Quaglia and Francesco Tabaro and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85072180336&origin=inward},

doi = {10.1007/s00726-019-02781-8},

year  = {2019},

date = {2019-01-01},

journal = {Amino Acids},

volume = {51},

number = {10-12},

pages = {1461-1474},

publisher = {Springer},

abstract = {© 2019, Springer-Verlag GmbH Austria, part of Springer Nature.We present an in silico characterization of the von Hippel–Lindau-like protein (VLP), the only known human paralog of the von Hippel–Lindau tumor suppressor protein (pVHL). Phylogenetic investigation showed VLP to be mostly conserved in upper mammals and specifically expressed in brain and testis. Structural analysis and molecular dynamics simulations show VLP to be very similar to pVHL three-dimensional organization and binding dynamics. In particular, conservation of elements at the protein interfaces suggests VLP to be a functional pVHL homolog potentially possessing multiple functions beyond HIF-1α-dependent binding activity. Our findings show that VLP may share at least seven interactors with pVHL, suggesting novel functional roles for this understudied human protein. These may occur at precise hypoxia levels where functional overlap with pVHL may permit a finer modulation of pVHL functions.},

note = {Cited by: 6},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85066429584,

title = {In silico characterization of human prion-like proteins: Beyond neurological diseases},

author = {Valentin Iglesias and Lisanna Paladin and Teresa Juan-Blanco and Irantzu Pallarès and Patrick Aloy and Silvio C. E. Tosatto and Salvador Ventura},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85066429584&origin=inward},

doi = {10.3389/fphys.2019.00314},

year  = {2019},

date = {2019-01-01},

journal = {Frontiers in Physiology},

volume = {10},

number = {MAR},

publisher = {Frontiers Media S.A.info@frontiersin.org},

abstract = {© 2019 Iglesias, Paladin, Juan-Blanco, Pallarès, Aloy, Tosatto and Ventura.Prion-like behavior has been in the spotlight since it was first associated with the onset of mammalian neurodegenerative diseases. However, a growing body of evidence suggests that this mechanism could be behind the regulation of processes such as transcription and translation in multiple species. Here, we perform a stringent computational survey to identify prion-like proteins in the human proteome. We detected 242 candidate polypeptides and computationally assessed their function, protein-protein interaction networks, tissular expression, and their link to disease. Human prion-like proteins constitute a subset of modular polypeptides broadly expressed across different cell types and tissues, significantly associated with disease, embedded in highly connected interaction networks, and involved in the flow of genetic information in the cell. Our analysis suggests that these proteins might play a relevant role not only in neurological disorders, but also in different types of cancer and viral infections.},

note = {Cited by: 17; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85060866810,

title = {The lipoprotein HP1454 of Helicobacter pylori regulates T-cell response by shaping T-cell receptor signalling},

author = {Nagaja Capitani and Gaia Codolo and Francesca Vallese and Giovanni Minervini and Alessia Grassi and Fabio Cianchi and Arianna Troilo and Wolfgang Fischer and Giuseppe Zanotti and Cosima T. Baldari and Marina Bernard and Mario M. D'Elios},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85060866810&origin=inward},

doi = {10.1111/cmi.13006},

year  = {2019},

date = {2019-01-01},

journal = {Cellular Microbiology},

volume = {21},

number = {5},

publisher = {Blackwell Publishing Ltd},

abstract = {© 2019 John Wiley & Sons LtdHelicobacter pylori (HP) is a Gram-negative bacterium that chronically infects the stomach of more than 50% of human population and represents a major cause of gastric cancer, gastric lymphoma, gastric autoimmunity, and peptic ulcer. It still remains to be elucidated, which HP virulence factors are important in the development of gastric disorders. Here, we analysed the role of the HP protein HP1454 in the host–pathogen interaction. We found that a significant proportion of T cells isolated from HP patients with chronic gastritis and gastric adenocarcinoma proliferated in response to HP1454. Moreover, we demonstrated in vivo that HP1454 protein drives Th1/Th17 inflammatory responses. We further analysed the in vitro response of human T cells exposed either to an HP wild-type strain or to a strain with a deletion of the hp1454 gene, and we revealed that HP1454 triggers the T-cell antigen receptor-dependent signalling and lymphocyte proliferation, as well as the CXCL12-dependent cell adhesion and migration. Our study findings prove that HP1454 is a crucial bacterial factor that exerts its proinflammatory activity by directly modulating the T-cell response. The relevance of these results can be appreciated by considering that compelling evidence suggest that chronic gastric inflammation, a condition that paves the way to HP-associated diseases, is dependent on T cells.},

note = {Cited by: 36; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85064958529,

title = {Genotype-phenotype relations of the von hippel-lindau tumor suppressor inferred from a large-scale analysis of disease mutations and interactors},

author = {Giovanni Minervini and Federica Quaglia and Francesco Tabaro and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85064958529&origin=inward},

doi = {10.1371/journal.pcbi.1006478},

year  = {2019},

date = {2019-01-01},

journal = {PLoS Computational Biology},

volume = {15},

number = {4},

publisher = {Public Library of Science},

abstract = {© 2019 Minervini et al.Familiar cancers represent a privileged point of view for studying the complex cellular events inducing tumor transformation. Von Hippel-Lindau syndrome, a familiar predisposition to develop cancer is a clear example. Here, we present our efforts to decipher the role of von Hippel-Lindau tumor suppressor protein (pVHL) in cancer insurgence. We collected high quality information about both pVHL mutations and interactors to investigate the association between patient phenotypes, mutated protein surface and impaired interactions. Our data suggest that different phenotypes correlate with localized perturbations of the pVHL structure, with specific cell functions associated to different protein surfaces. We propose five different pVHL interfaces to be selectively involved in modulating proteins regulating gene expression, protein homeostasis as well as to address extracellular matrix (ECM) and ciliogenesis associated functions. These data were used to drive molecular docking of pVHL with its interactors and guide Petri net simulations of the most promising alterations. We predict that disruption of pVHL association with certain interactors can trigger tumor transformation, inducing metabolism imbalance and ECM remodeling. Collectively taken, our findings provide novel insights into VHL-associated tumorigenesis. This highly integrated in silico approach may help elucidate novel treatment paradigms for VHL disease.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85041358932,

title = {Large scale analysis of protein conformational transitions from aqueous to non-aqueous media},

author = {Ana Julia Velez Rueda and Alexander Miguel Monzon and Sebastián M. Ardanaz and Luis E. Iglesias and Gustavo Parisi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85041358932&origin=inward},

doi = {10.1186/s12859-018-2044-2},

year  = {2018},

date = {2018-01-01},

journal = {BMC Bioinformatics},

volume = {19},

number = {1},

publisher = {BioMed Central Ltd.info@biomedcentral.com},

abstract = {© 2018 The Author(s).Background: Biocatalysis in organic solvents is nowadays a common practice with a large potential in Biotechnology. Several studies report that proteins which are co-crystallized or soaked in organic solvents preserve their fold integrity showing almost identical arrangements when compared to their aqueous forms. However, it is well established that the catalytic activity of proteins in organic solvents is much lower than in water. In order to explain this diminished activity and to further characterize the behaviour of proteins in non-aqueous environments, we performed a large-scale analysis (1737 proteins) of the conformational diversity of proteins crystallized in aqueous and co-crystallized or soaked in non-aqueous media. Results: Using proteins' experimentally determined conformational diversity taken from CoDNaS database, we found that proteins in non-aqueous media display much lower conformational diversity when compared to the corresponding conformers obtained in water. When conformational diversity is compared between conformers obtained in different non-aqueous media, their structural differences are larger and mostly independent of the presence of cognate ligands. We also found that conformers corresponding to non-aqueous media have larger but less flexible cavities, lower number of disordered regions and lower active-site residue mobility. Conclusions: Our results show that non-aqueous media conformers have specific structural features and that they do not adopt extreme conformations found in aqueous media. This makes them clearly different from their corresponding aqueous conformers.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85056649648,

title = {High-conductance channel formation in yeast mitochondria is mediated by F-ATP synthase e and g subunits},

author = {Michela Carraro and Vanessa Checchetto and Geppo Sartori and Roza Kucharczyk and Jean-Paul Di Rago and Giovanni Minervini and Cinzia Franchin and Giorgio Arrigoni and Valentina Giorgio and Valeria Petronilli and Silvio C. E. Tosatto and Giovanna Lippe and Ildikó Szabó and Paolo Bernardi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85056649648&origin=inward},

doi = {10.1159/000494864},

year  = {2018},

date = {2018-01-01},

journal = {Cellular Physiology and Biochemistry},

volume = {50},

number = {5},

pages = {1840-1855},

publisher = {S. Karger AGeditor@cellphysiolbiochem.com},

abstract = {© 2018 The Author(s). Published by S. Karger AG, Basel. Background/Aims: The permeability transition pore (PTP) is an unselective, Ca 2+ -dependent high conductance channel of the inner mitochondrial membrane whose molecular identity has long remained a mystery. The most recent hypothesis is that pore formation involves the F-ATP synthase, which consistently generates Ca 2+ -activated channels. Available structures do not display obvious features that can accommodate a channel; thus, how the pore can form and whether its activity can be entirely assigned to F-ATP synthase is the matter of debate. In this study, we investigated the role of F-ATP synthase subunits e, g and b in PTP formation. Methods: Yeast null mutants for e, g and the first transmembrane (TM) α-helix of subunit b were generated and evaluated for mitochondrial morphology (electron microscopy), membrane potential (Rhodamine123 fluorescence) and respiration (Clark electrode). Homoplasmic C23S mutant of subunit a was generated by in vitro mutagenesis followed by biolistic transformation. F-ATP synthase assembly was evaluated by BN-PAGE analysis. Cu 2+ treatment was used to induce the formation of F-ATP synthase dimers in the absence of e and g subunits. The electrophysiological properties of F-ATP synthase were assessed in planar lipid bilayers. Results: Null mutants for the subunits e and g display dimer formation upon Cu 2+ treatment and show PTP-dependent mitochondrial Ca 2+ release but not swelling. Cu 2+ treatment causes formation of disulfide bridges between Cys23 of subunits a that stabilize dimers in absence of e and g subunits and favors the open state of wild-type F-ATP synthase channels. Absence of e and g subunits decreases conductance of the F-ATP synthase channel about tenfold. Ablation of the first TM of subunit b, which creates a distinct lateral domain with e and g, further affected channel activity. Conclusion: F-ATP synthase e, g and b subunits create a domain within the membrane that is critical for the generation of the high-conductance channel, thus is a prime candidate for PTP formation. Subunits e and g are only present in eukaryotes and may have evolved to confer this novel function to F-ATP synthase.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85055609950,

title = {Whole-Exome Sequencing Identifies Pathogenic Variants in TJP1 Gene Associated With Arrhythmogenic Cardiomyopathy},

author = {Marzia De Bortoli and Alex V. Postma and Giulia Poloni and Martina Calore and Giovanni Minervini and Elisa Mazzotti and Ilaria Rigato and Micaela Ebert and Alessandra Lorenzon and Giovanni Vazza and Alberto Cipriani and Riccardo Bariani and Martina Perazzolo Marra and Daniela Husser and Gaetano Thiene and Luciano Daliento and Domenico Corrado and Cristina Basso and Silvio C E Tosatto and Barbara Bauce and J Peter Tintelen and Alessandra Rampazzo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85055609950&origin=inward},

doi = {10.1161/CIRCGEN.118.002123},

year  = {2018},

date = {2018-01-01},

journal = {Circulation. Genomic and precision medicine},

volume = {11},

number = {10},

publisher = {NLM (Medline)},

abstract = {BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by progressive fibro-fatty myocardial replacement, ventricular arrhythmia, heart failure, and sudden death. Causative mutations can be identified in 60% of patients, and most of them are found in genes encoding mechanical junction proteins of the intercalated disk. METHODS: Whole-exome sequencing was performed on the proband of an ACM family. Sanger sequencing was used to screen for mutations the tight junction protein 1 ( TJP1) gene in unrelated patients. Predictions of local structure content and molecular dynamics simulations were performed to investigate the structural impact of the variants. RESULTS: A novel c.2006A>G p.(Y669C) variant in TJP1 gene was identified by whole-exome sequencing in a patient with ACM. TJP1 encodes zonula occludens 1, an intercalated disk protein interacting with proteins of gap junctions and area composita. Additional rare TJP1 variants have been identified in 1 of 40 Italian probands (c.793C>T p.(R265W)) with arrhythmogenic right ventricular cardiomyopathy and in 2 of 43 Dutch/German patients (c. 986C>T, p.(S329L) and c.1079A>T, p.(D360V)) with dilated cardiomyopathy and recurrent ventricular tachycardia. The p.(D360V) variant was identified in a proband also carrying the p.(I156N) pathogenic variant in DSP. All 4 TJP1 variants are predicted to be deleterious and affect highly conserved amino acids, either at the GUK (guanylate kinase)-like domain (p.(Y669C)) or at the disordered region of the protein between the PDZ2 and PDZ3 domains (p.(R265W), p.(S329L), and p.(D360V)). The local unfolding induced by the former promotes structural rearrangements of the GUK domain, whereas the others are predicted to impair the function of the disordered region. Furthermore, rare variants in TJP1 are statistically enriched in patients with ACM relative to controls. CONCLUSIONS: We provide here the first evidence linking likely pathogenic TJP1 variants to ACM. Prevalence and pathogenic mechanism of TJP1-mediated ACM remain to be determined.},

note = {Cited by: 37; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85031328493,

title = {Classification of β-hairpin repeat proteins},

author = {Daniel B. Roche and Phuong Do Viet and Anastasia Bakulina and Layla Hirsh and Silvio C. E. Tosatto and Andrey V. Kajava},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85031328493&origin=inward},

doi = {10.1016/j.jsb.2017.10.001},

year  = {2018},

date = {2018-01-01},

journal = {Journal of Structural Biology},

volume = {201},

number = {2},

pages = {130-138},

publisher = {Academic Press Inc.apjcs@harcourt.com},

abstract = {© 2017 Elsevier Inc.In recent years, a number of new protein structures that possess tandem repeats have emerged. Many of these proteins are comprised of tandem arrays of β-hairpins. Today, the amount and variety of the data on these β-hairpin repeat (BHR) structures have reached a level that requires detailed analysis and further classification. In this paper, we classified the BHR proteins, compared structures, sequences of repeat motifs, functions and distribution across the major taxonomic kingdoms of life and within organisms. As a result, we identified six different BHR folds in tandem repeat proteins of Class III (elongated structures) and one BHR fold (up-and-down β-barrel) in Class IV (“closed” structures). Our survey reveals the high incidence of the BHR proteins among bacteria and viruses and their possible relationship to the structures of amyloid fibrils. It indicates that BHR folds will be an attractive target for future structural studies, especially in the context of age-related amyloidosis and emerging infectious diseases. This work allowed us to update the RepeatsDB database, which contains annotated tandem repeat protein structures and to construct sequence profiles based on BHR structural alignments.},

note = {Cited by: 18},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85054779412,

title = {Reflections on a journey: a retrospective of the ISCB Student Council symposium series},

author = {Mehedi Hassan and Aishwarya Alex Namasivayam and Dan DeBlasio and Nazeefa Fatima and Benjamin Siranosian and R Gonzalo Parra and Bart Cuypers and Sayane Shome and Alexander Miguel Monzon and Julien Fumey and Farzana Rahman},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85054779412&origin=inward},

doi = {10.1186/s12859-018-2369-x},

year  = {2018},

date = {2018-01-01},

journal = {BMC bioinformatics},

volume = {19},

publisher = {NLM (Medline)},

abstract = {This article describes the motivation, origin and evolution of the student symposia series organised by the ISCB Student Council. The meeting series started thirteen years ago in Madrid and has spread to four continents. The article concludes with the highlights of the most recent edition of annual Student Council Symposium held in conjunction with the 25th Conference on Intelligent Systems for Molecular Biology and the 16th European Conference on Computational Biology, in Prague, in July 2017.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85054013935,

title = {Arginine 107 of yeast ATP synthase subunit g mediates sensitivity of the mitochondrial permeability transition to phenylglyoxal},

author = {Lishu Guo and Michela Carraro and Geppo Sartori and Giovanni Minervini and Ove Eriksson and Valeria Petronilli and Paolo Bernardi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85054013935&origin=inward},

doi = {10.1074/jbc.RA118.004495},

year  = {2018},

date = {2018-01-01},

journal = {Journal of Biological Chemistry},

volume = {293},

number = {38},

pages = {14632-14645},

publisher = {American Society for Biochemistry and Molecular Biology Inc.9650 Rockville PikeBethesdaMD 20814},

abstract = {© 2018 Guo et al.Modification with arginine-specific glyoxals modulates the permeability transition (PT) of rat liver mitochondria, with inhibitory or inducing effects that depend on the net charge of the adduct(s). Here, we show that phenylglyoxal (PGO) affects the PT in a species-specific manner (inhibition in mouse and yeast, induction in human and Drosophila mitochondria). Following the hypotheses (i) that the effects are mediated by conserved arginine(s) and (ii) that the PT is mediated by the F-ATP synthase, we have narrowed the search to 60 arginines. Most of these residues are located in subunits α, β, γ, ϵ, a, and c and were excluded because PGO modification did not significantly affect enzyme catalysis. On the other hand, yeast mitochondria lacking subunit g or bearing a subunit g R107A mutation were totally resistant to PT inhibition by PGO. Thus, the effect of PGO on the PT is specifically mediated by Arg-107, the only subunit g arginine that has been conserved across species. These findings are evidence that the PT is mediated by F-ATP synthase.},

note = {Cited by: 43; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85055165346,

title = {The clinical spectrum of CASQ1-related myopathy},

author = {Claudio Semplicini and Cinzia Bertolin and Luca Bello and Boris Pantic and Francesca Guidolin and Sara Vianello and Francesco Catapano and Irene Colombo and Maurizio Moggio and Bruno F. Gavassini and Giovanna Cenacchi and Valentina Papa and Marco Previtero and Chiara Calore and Gianni Sorarù and Giovanni Minervini and Silvio C. E. Tosatto and Roberto Stramare and Elena Pegoraro},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85055165346&origin=inward},

doi = {10.1212/WNL.0000000000006387},

year  = {2018},

date = {2018-01-01},

journal = {Neurology},

volume = {91},

number = {17},

pages = {E1629-E1641},

publisher = {Lippincott Williams and Wilkinskathiest.clai@apta.org},

abstract = {Copyright © 2018 American Academy of NeurologyObjective To identify and characterize patients with calsequestrin 1 (CASQ1)-related myopathy. Methods Patients selected according to histopathologic features underwent CASQ1 genetic screening. CASQ1-mutated patients were clinically evaluated and underwent muscle MRI. Vacuole morphology and vacuolated fiber type were characterized. Results Twenty-two CASQ1-mutated patients (12 families) were identified, 21 sharing the previously described founder mutation (p.Asp244Gly) and 1 with the p.Gly103Asp mutation. Patients usually presented in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging. Muscle MRI (n = 11) showed a recurrent fibrofatty substitution pattern. Three patients presented subclinical cardiac abnormalities. Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins. The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates. Conclusions We report the clinical and molecular details of the largest cohort of CASQ1-mutated patients. A possible heart involvement is presented, further expanding the phenotype of the disease. One mutation is common due to a founder effect, but other mutations are possible. Because of a paucity of symptoms, it is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed.},

note = {Cited by: 23},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85041417606,

title = {A comprehensive assessment of long intrinsic protein disorder from the DisProt database},

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

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85041417606&origin=inward},

doi = {10.1093/bioinformatics/btx590},

year  = {2018},

date = {2018-01-01},

journal = {Bioinformatics},

volume = {34},

number = {3},

pages = {445-452},

publisher = {Oxford University Pressjnl.info@oup.co.uk},

abstract = {© The Author 2017.Motivation Intrinsic disorder (ID), i.e.The lack of a unique folded conformation at physiological conditions, is a common feature for many proteins, which requires specialized biochemical experiments that are not high-Throughput. Missing X-ray residues from the PDB have been widely used as a proxy for ID when developing computational methods. This may lead to a systematic bias, where predictors deviate from biologically relevant ID. Large benchmarking sets on experimentally validated ID are scarce. Recently, the DisProt database has been renewed and expanded to include manually curated ID annotations for several hundred new proteins. This provides a large benchmark set which has not yet been used for training ID predictors. Results Here, we describe the first systematic benchmarking of ID predictors on the new DisProt dataset. In contrast to previous assessments based on missing X-ray data, this dataset contains mostly long ID regions and a significant amount of fully ID proteins. The benchmarking shows that ID predictors work quite well on the new dataset, especially for long ID segments. However, a large fraction of ID still goes virtually undetected and the ranking of methods is different than for PDB data. In particular, many predictors appear to confound ID and regions outside X-ray structures. This suggests that the ID prediction methods capture different flavors of disorder and can benefit from highly accurate curated examples.},

note = {Cited by: 53; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85049094679,

title = {How is structural divergence related to evolutionary information?},

author = {Diego Javier Zea and Alexander Miguel Monzon and Gustavo Parisi and Cristina Marino-Buslje},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85049094679&origin=inward},

doi = {10.1016/j.ympev.2018.06.033},

year  = {2018},

date = {2018-01-01},

journal = {Molecular Phylogenetics and Evolution},

volume = {127},

pages = {859-866},

publisher = {Academic Press Inc.apjcs@harcourt.com},

abstract = {© 2018 Elsevier Inc.The analysis of evolutionary information in a protein family, such as conservation and covariation, is often linked to its structural information. Multiple sequence alignments of distant homologous sequences are used to measure evolutionary variables. Although high structural differences between proteins can be expected in such divergent alignments, most works linking evolutionary and structural information use a single structure ignoring the structural variability within protein families. The goal of this work is to elucidate the relevance of structural divergence when sequence-based measures are integrated with structural information. We found that inter-residue contacts and solvent accessibility undergo large variations in protein families. Our results show that high covariation scores tend to reveal residue contacts that are conserved in the family, instead of protein or conformer specific contacts. We also found that residue accessible surface area shows a high variability between structures of the same family. As a consequence, the mean relative solvent accessibility of multiple structures correlates better with the conservation pattern than the relative solvent accessibility of a single structure. We conclude that the use of comprehensive structural information allows a more accurate interpretation of the information computed from sequence alignments. Therefore, considering structural divergence would lead to a better understanding of protein function, dynamics, and evolution.},

note = {Cited by: 11},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85040952194,

title = {MobiDB 3.0: More annotations for intrinsic disorder, conformational diversity and interactions in proteins},

author = {Damiano Piovesan and Francesco Tabaro and Lisanna Paladin and Marco Necci and Ivan Mičetić and Carlo Camilloni and Norman Davey and Zsuzsanna Dosztányi and Bálint Mészáros and Alexander M Monzon and Gustavo Parisi and Eva Schad and Pietro Sormanni and Peter Tompa and Michele Vendruscolo and Wim F Vranken and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85040952194&origin=inward},

doi = {10.1093/nar/gkx1071},

year  = {2018},

date = {2018-01-01},

journal = {Nucleic Acids Research},

volume = {46},

number = {D1},

pages = {D471-D476},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.The MobiDB (URL: mobidb.bio.unipd.it) database of protein disorder and mobility annotations has been significantly updated and upgraded since its last major renewal in 2014. Several curated datasets for intrinsic disorder and folding upon binding have been integrated from specialized databases. The indirect evidence has also been expanded to better capture information available in the PDB, such as high temperature residues in X-ray structures and overall conformational diversity. Novel nuclear magnetic resonance chemical shift data provides an additional experimental information layer on conformational dynamics. Predictions have been expanded to provide new types of annotation on backbone rigidity, secondary structure preference and disordered binding regions. MobiDB 3.0 contains information for the complete UniProt protein set and synchronization has been improved by covering all UniParc sequences. An advanced search function allows the creation of a wide array of custom-made datasets for download and further analysis. A large amount of information and cross-links to more specialized databases are intended to make MobiDB the central resource for the scientific community working on protein intrinsic disorder and mobility.},

note = {Cited by: 168; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85054843058,

title = {Calmodulin Enhances Cryptochrome Binding to INAD in Drosophila Photoreceptors},

author = {Gabriella Margherita Mazzotta and Massimo Bellanda and Giovanni Minervini and Milena Damulewicz and Paola Cusumano and Simona Aufiero and Monica Stefani and Barbara Zambelli and Stefano Mammi and Rodolfo Costa and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85054843058&origin=inward},

doi = {10.3389/fnmol.2018.00280},

year  = {2018},

date = {2018-01-01},

journal = {Frontiers in Molecular Neuroscience},

volume = {11},

publisher = {Frontiers Media S.A.info@frontiersin.org},

abstract = {© 2018 Mazzotta, Bellanda, Minervini, Damulewicz, Cusumano, Aufiero, Stefani, Zambelli, Mammi, Costa and Tosatto.Light is the main environmental stimulus that synchronizes the endogenous timekeeping systems in most terrestrial organisms. Drosophila cryptochrome (dCRY) is a light-responsive flavoprotein that detects changes in light intensity and wavelength around dawn and dusk. We have previously shown that dCRY acts through Inactivation No Afterpotential D (INAD) in a light-dependent manner on the Signalplex, a multiprotein complex that includes visual-signaling molecules, suggesting a role for dCRY in fly vision. Here, we predict and demonstrate a novel Ca2+-dependent interaction between dCRY and calmodulin (CaM). Through yeast two hybrid, coimmunoprecipitation (Co-IP), nuclear magnetic resonance (NMR) and calorimetric analyses we were able to identify and characterize a CaM binding motif in the dCRY C-terminus. Similarly, we also detailed the CaM binding site of the scaffold protein INAD and demonstrated that CaM bridges dCRY and INAD to form a ternary complex in vivo. Our results suggest a process whereby a rapid dCRY light response stimulates an interaction with INAD, which can be further consolidated by a novel mechanism regulated by CaM.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85040086967,

title = {Mobi 2.0: An improved method to define intrinsic disorder, mobility and linear binding regions in protein structures},

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

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85040086967&origin=inward},

doi = {10.1093/bioinformatics/btx592},

year  = {2018},

date = {2018-01-01},

journal = {Bioinformatics},

volume = {34},

number = {1},

pages = {122-123},

publisher = {Oxford University Pressjnl.info@oup.co.uk},

abstract = {© 2017 The Author.Motivation: The structures contained in the Protein Data Bank (PDB) database are of paramount importance to define our knowledge of folded proteins. While providing mainly circumstantial evidence, PDB data is also increasingly used to define the lack of unique structure, represented by mobile regions and even intrinsic disorder (ID). However, alternative definitions are used by different authors and potentially limit the generality of the analyses being carried out. Results: Here we present Mobi 2.0, a completely re-written version of the Mobi software for the determination of mobile and potentially disordered regions from PDB structures. Mobi 2.0 provides robust definitions of mobility based on four main sources of information: (i) missing residues, (ii) residues with high temperature factors, (iii) mobility between different models of the same structure and (iv) binding to another protein or nucleotide chain. Mobi 2.0 is well suited to aggregate information across different PDB structures for the same UniProt protein sequence, providing consensus annotations. The software is expected to standardize the treatment of mobility, allowing an easier comparison across different studies related to ID.},

note = {Cited by: 23; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85039804619,

title = {Editorial for special issue “Proteins with tandem repeats: sequences, structures and functions”},

author = {Andrey V. Kajava and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85039804619&origin=inward},

doi = {10.1016/j.jsb.2017.12.011},

year  = {2018},

date = {2018-01-01},

journal = {Journal of Structural Biology},

volume = {201},

number = {2},

pages = {86-87},

publisher = {Academic Press Inc.apjcs@harcourt.com},

note = {Cited by: 6},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85058916010,

title = {PhytoTypeDB: a database of plant protein inter-cultivar variability and function},

author = {Marco Necci and Damiano Piovesan and Diego Micheletti and Lisanna Paladin and Alessandro Cestaro and Silvio C E Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85058916010&origin=inward},

doi = {10.1093/database/bay125},

year  = {2018},

date = {2018-01-01},

journal = {Database : the journal of biological databases and curation},

volume = {2018},

publisher = {NLM (Medline)},

abstract = {Despite a fast-growing number of available plant genomes, available computational resources are poorly integrated and provide only limited access to the underlying data. Most existing databases focus on DNA/RNA data or specific gene families, with less emphasis on protein structure, function and variability. In particular, despite the economic importance of many plant accessions, there are no straightforward ways to retrieve or visualize information on their differences. To fill this gap, we developed PhytoTypeDB (http://phytotypedb.bio.unipd.it/), a scalable database containing plant protein annotations and genetic variants from resequencing of different accessions. The database content is generated by an integrated pipeline, exploiting state-of-the-art methods for protein characterization requiring only the proteome reference sequence and variant calling files. Protein names for unknown proteins are inferred by homology for over 95% of the entries. Single-nucleotide variants are visualized along with protein annotation in a user-friendly web interface. The server offers an effective querying system, which allows to compare variability among different species and accessions, to generate custom data sets based on shared functional features or to perform sequence searches. A documented set of exposed RESTful endpoints make the data accessible programmatically by third-party clients.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85034860326,

title = {CNTNAP2 mutations and autosomal dominant epilepsy with auditory features},

author = {Emanuela Leonardi and Emanuela Dazzo and Maria Cristina Aspromonte and Francesco Tabaro and Stefano Pascarelli and Silvio C. E. Tosatto and Roberto Michelucci and Alessandra Murgia and Carlo Nobile},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85034860326&origin=inward},

doi = {10.1016/j.eplepsyres.2017.11.006},

year  = {2018},

date = {2018-01-01},

journal = {Epilepsy Research},

volume = {139},

pages = {51-53},

publisher = {Elsevier B.V.},

abstract = {© 2017 Elsevier B.V.Autosomal dominant epilepsy with auditory features (ADEAF) is clinically characterized by focal seizures with prominent auditory or aphasic auras and absence of structural brain abnormalities. Mutations in LGI1 and RELN genes account for the disorder in about 50% of ADEAF families. In a recent paper, a heterozygous intragenic deletion in the CNTNAP2 gene has been associated to ADEAF in a single family. We screened 28 ADEAF families for mutations in CNTNAP2 by next generation sequencing and copy number variation analyses and found no likely pathogenic mutations segregating with the disease. CNTNAP2 should be screened in genetically unsolved ADEAF families, but causative mutations are expected to be infrequent in this gene.},

note = {Cited by: 4},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85050871019,

title = {RepeatsDB-lite: A web server for unit annotation of tandem repeat proteins},

author = {Layla Hirsh and Lisanna Paladin and Damiano Piovesan and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85050871019&origin=inward},

doi = {10.1093/nar/gky360},

year  = {2018},

date = {2018-01-01},

journal = {Nucleic Acids Research},

volume = {46},

number = {W1},

pages = {W402-W407},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.RepeatsDB-lite (http://protein.bio.unipd.it/repeatsdb-lite) is a web server for the prediction of repetitive structural elements and units in tandem repeat (TR) proteins. TRs are a widespread but poorly annotated class of non-globular proteins carrying heterogeneous functions. RepeatsDB-lite extends the prediction to all TR types and strongly improves the performance both in terms of computational time and accuracy over previous methods, with precision above 95% for solenoid structures. The algorithm exploits an improved TR unit library derived from the RepeatsDB database to perform an iterative structural search and assignment. The web interface provides tools for analyzing the evolutionary relationships between units and manually refine the prediction by changing unit positions and protein classification. An all-against-all structure-based sequence similarity matrix is calculated and visualized in real-time for every user edit. Reviewed predictions can be submitted to RepeatsDB for review and inclusion.},

note = {Cited by: 19; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85058907124,

title = {Where differences resemble: sequence-feature analysis in curated databases of intrinsically disordered proteins},

author = {Marco Necci and Damiano Piovesan and Silvio C E Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85058907124&origin=inward},

doi = {10.1093/database/bay127},

year  = {2018},

date = {2018-01-01},

journal = {Database : the journal of biological databases and curation},

volume = {2018},

publisher = {NLM (Medline)},

abstract = {Intrinsic disorder (ID) in proteins is involved in crucial interactions in the living cell. As the importance of ID is increasingly recognized, so are detailed analyses aimed at its identification and characterization. An open question remains the existence of ID `flavors' representing different sub-phenomena. Several databases collect manually curated examples of experimentally validated ID, focusing on apparently different aspects of this phenomenon. The recent update of MobiDB presented the opportunity to carry out an in-depth comparison of the content of these validated ID collections, namely DIBS, DisProt, IDEAL, MFIB, FuzDB, ELM and UniProt. In order to assess what is specific to different ID flavors, we analyzed relevant sequence-based features, such as amino acid composition, length, taxa and gene ontology terms, highlighting differences and similarities among datasets. Despite that, the majority of the considered features are not statistically different across databases, with the exception of ELM. FuzDB also shares half of its entries with DisProt. In general, different ID databases describe similar phenomena. DisProt, which is the largest database, better represents the entire spectrum of different disorder flavors and the corresponding sequence diversity.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85020465075,

title = {Lessons from the CAGI-4 Hopkins clinical panel challenge},

author = {John-Marc Chandonia and Aashish Adhikari and Marco Carraro and Aparna Chhibber and Garry R. Cutting and Yao Fu and Alessandra Gasparini and David T. Jones and Andreas Kramer and Kunal Kundu and Hugo Y. K. Lam and Emanuela Leonardi and John Moult and Lipika R. Pal and David B. Searls and Sohela Shah and Shamil Sunyaev and Silvio C. E. Tosatto and Yizhou Yin and Bethany A. Buckley},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85020465075&origin=inward},

doi = {10.1002/humu.23225},

year  = {2017},

date = {2017-01-01},

journal = {Human Mutation},

volume = {38},

number = {9},

pages = {1155-1168},

publisher = {John Wiley and Sons Inc},

abstract = {© 2017 Wiley Periodicals, Inc.The CAGI-4 Hopkins clinical panel challenge was an attempt to assess state-of-the-art methods for clinical phenotype prediction from DNA sequence. Participants were provided with exonic sequences of 83 genes for 106 patients from the Johns Hopkins DNA Diagnostic Laboratory. Five groups participated in the challenge, predicting both the probability that each patient had each of the 14 possible classes of disease, as well as one or more causal variants. In cases where the Hopkins laboratory reported a variant, at least one predictor correctly identified the disease class in 36 of the 43 patients (84%). Even in cases where the Hopkins laboratory did not find a variant, at least one predictor correctly identified the class in 39 of the 63 patients (62%). Each prediction group correctly diagnosed at least one patient that was not successfully diagnosed by any other group. We discuss the causal variant predictions by different groups and their implications for further development of methods to assess variants of unknown significance. Our results suggest that clinically relevant variants may be missed when physicians order small panels targeted on a specific phenotype. We also quantify the false-positive rate of DNA-guided analysis in the absence of prior phenotypic indication.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85024484623,

title = {A community proposal to integrate proteomics activities in ELIXIR},

author = {Juan Antonio Vizcaíno and Mathias Walzer and Rafael C. Jiménez and Wout Bittremieux and David Bouyssié and Christine Carapito and Fernando Corrales and Myriam Ferro and Albert J. R. Heck and Peter Horvatovich and Martin Hubalek and Lydie Lane and Kris Laukens and Fredrik Levander and Frederique Lisacek and Petr Novak and Magnus Palmblad and Damiano Piovesan and Alfred Pühler and Veit Schwämmle and Dirk Valkenborg and Merlijn Rijswijk and Jiri Vondrasek and Martin Eisenacher and Lennart Martens and Oliver Kohlbacher},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85024484623&origin=inward},

doi = {10.12688/f1000research.11751.1},

year  = {2017},

date = {2017-01-01},

journal = {F1000Research},

volume = {6},

publisher = {Faculty of 1000 Ltdinfo@f1000.com},

abstract = {© 2017 Vizcaíno JA et al.Computational approaches have been major drivers behind the progress of proteomics in recent years. The aim of this white paper is to provide a framework for integrating computational proteomics into ELIXIR in the near future, and thus to broaden the portfolio of omics technologies supported by this European distributed infrastructure. This white paper is the direct result of a strategy meeting on 'The Future of Proteomics in ELIXIR' that took place in March 2017 in Tübingen (Germany), and involved representatives of eleven ELIXIR nodes. These discussions led to a list of priority areas in computational proteomics that would complement existing activities and close gaps in the portfolio of tools and services offered by ELIXIR so far. We provide some suggestions on how these activities could be integrated into ELIXIR's existing platforms, and how it could lead to a new ELIXIR use case in proteomics. We also highlight connections to the related field of metabolomics, where similar activities are ongoing. This white paper could thus serve as a starting point for the integration of computational proteomics into ELIXIR. Over the next few months we will be working closely with all stakeholders involved, and in particular with other representatives of the proteomics community, to further refine this paper.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85020523355,

title = {In silico study of the structure and function of Streptococcus mutans plasmidic proteins},

author = {Silvia Caprari and Giovanni Minervini and Valentina Brandi and Fabio Polticelli},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85020523355&origin=inward},

doi = {10.1515/bams-2017-0012},

year  = {2017},

date = {2017-01-01},

journal = {Bio-Algorithms and Med-Systems},

volume = {13},

number = {2},

pages = {51-61},

publisher = {Walter de Gruyter GmbH},

abstract = {© 2017 Walter de Gruyter GmbH, Berlin/Boston 2017.The Gram-positive bacterium Streptococcus mutans is the principal causative agent of human tooth decay, an oral disease that affects the majority of the world's population. Although the complete S. mutans genome is known, approximately 700 proteins are still annotated as hypothetical proteins, as no three-dimensional structure or homology with known proteins exists for them. Thus, the significant portion of genomic sequences coding for unknown-function proteins makes the knowledge of pathogenicity and survival mechanisms of S. mutans still incomplete. Plasmids are found in virtually every species of Streptococcus, and some of these mediate resistance to antibiotics and pathogenesis. However, there are strains of S. mutans that contain plasmids, such as LM7 and UA140, to which no function has been assigned yet. In this work, we describe an in silico study of the structure and function of all the S. mutans proteins encoded by pLM7 and pUA140 plasmids to gain insight into their biological function. A combination of different structural bioinformatics methodologies led to the identification of plasmidic proteins potentially required for the bacterial survival and pathogenicity. The structural information obtained on these proteins can be used to select novel targets for the design of innovative therapeutic agents towards S. mutans.},

note = {Cited by: 0},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85016141786,

title = {InterPro in 2017-beyond protein family and domain annotations},

author = {Robert D. Finn and Teresa K. Attwood and Patricia C. Babbitt and Alex Bateman and Peer Bork and Alan J. Bridge and Hsin-Yu Chang and Zsuzsanna Dosztanyi and Sara El-Gebali and Matthew Fraser and Julian Gough and David Haft and Gemma L. Holliday and Hongzhan Huang and Xiaosong Huang and Ivica Letunic and Rodrigo Lopez and Shennan Lu and Aron Marchler-Bauer and Huaiyu Mi and Jaina Mistry and Darren A. Natale and Marco Necci and Gift Nuka and Christine A. Orengo and Youngmi Park and Sebastien Pesseat and Damiano Piovesan and Simon C. Potter and Neil D. Rawlings and Nicole Redaschi and Lorna Richardson and Catherine Rivoire and Amaia Sangrador-Vegas and Christian Sigrist and Ian Sillitoe and Ben Smithers and Silvano Squizzato and Granger Sutton and Narmada Thanki and Paul D. Thomas and Silvio C. E. Tosatto and Cathy H. Wu and Ioannis Xenarios and Lai-Su Yeh and Siew-Yit Young and Alex L. Mitchell},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85016141786&origin=inward},

doi = {10.1093/nar/gkw1107},

year  = {2017},

date = {2017-01-01},

journal = {Nucleic Acids Research},

volume = {45},

number = {D1},

pages = {D190-D199},

publisher = {Oxford University Pressjnl.info@oup.co.uk},

abstract = {© 2016 The Author(s).InterPro (http://www.ebi.ac.uk/interpro/) is a freely available database used to classify protein sequences into families and to predict the presence of important domains and sites. InterProScan is the underlying software that allows both protein and nucleic acid sequences to be searched against InterPro's predictive models, which are provided by its member databases. Here, we report recent developments with InterPro and its associated software, including the addition of two new databases (SFLD and CDD), and the functionality to include residue-level annotation and prediction of intrinsic disorder. These developments enrich the annotations provided by InterPro, increase the overall number of residues annotated and allow more specific functional inferences.},

note = {Cited by: 1202; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85029008824,

title = {Second ISCB Latin American Student Council Symposium (LA-SCS) 2016},

author = {Alexander Miguel Monzon and Marcia A. Hasenahuer and Estefanía Mancini and Nilson Coimbra and Fiorella Cravero and Javier Cáceres-Molina and César A Ramírez-Sarmiento and Nicolas Palopoli and Pieter Meysman and R Gonzalo Parra},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85029008824&origin=inward},

doi = {10.12688/f1000research.12321.1},

year  = {2017},

date = {2017-01-01},

journal = {F1000Research},

volume = {6},

publisher = {NLM (Medline)},

abstract = {This report summarizes the scientific content and activities of the second edition of the Latin American Symposium (LA-SCS), organized by the Student Council (SC) of the International Society for Computational Biology (ISCB), held in conjunction with the Fourth Latin American conference from the International Society for Computational Biology (ISCB-LA 2016) in Buenos Aires, Argentina, on November 19, 2016.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85023169351,

title = {SODA: Prediction of protein solubility from disorder and aggregation propensity},

author = {Lisanna Paladin and Damiano Piovesan and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85023169351&origin=inward},

doi = {10.1093/nar/gkx412},

year  = {2017},

date = {2017-01-01},

journal = {Nucleic Acids Research},

volume = {45},

number = {W1},

pages = {W236-W240},

publisher = {Oxford University Pressjnl.info@oup.co.uk},

abstract = {© 2017 The Author(s).Solubility is an important, albeit not well understood, feature determining protein behavior. It is of paramount importance in protein engineering, where similar folded proteins may behave in very different ways in solution. Here we present SODA, a novel method to predict the changes of protein solubility based on several physico-chemical properties of the protein. SODA uses the propensity of the protein sequence to aggregate as well as intrinsic disorder, plus hydrophobicity and secondary structure preferences to estimate changes in solubility. It has been trained and benchmarked on two different datasets. The comparison to other recently published methods shows that SODA has state-of-the-art performance and is particularly well suited to predict mutations decreasing solubility. The method is fast, returning results for single mutations in seconds. A usage example estimating the full repertoire of mutations for a human germline antibody highlights several solubility hotspots on the surface.},

note = {Cited by: 61; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85016112986,

title = {DisProt 7.0: A major update of the database of disordered proteins},

author = {Damiano Piovesan and Francesco Tabaro and Ivan Mičetić and Marco Necci and Federica Quaglia and Christopher J. Oldfield and Maria Cristina Aspromonte and Norman E. Davey and Radoslav Davidović and Zsuzsanna Dosztányi and Arne Elofsson and Alessandra Gasparini and András Hatos and Andrey V. Kajava and Lajos Kalmar and Emanuela Leonardi and Tamas Lazar and Sandra Macedo-Ribeiro and Mauricio Macossay-Castillo and Attila Meszaros and Giovanni Minervini and Nikoletta Murvai and Jordi Pujols and Daniel B. Roche and Edoardo Salladini and Eva Schad and Antoine Schramm and Beata Szabo and Agnes Tantos and Fiorella Tonello and Konstantinos D. Tsirigos and Nevena Veljković and Salvador Ventura and Wim Vranken and Per Warholm and Vladimir N. Uversky and A. Keith Dunker and Sonia Longhi and Peter Tompa and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85016112986&origin=inward},

doi = {10.1093/nar/gkw1056},

year  = {2017},

date = {2017-01-01},

journal = {Nucleic Acids Research},

volume = {45},

number = {D1},

pages = {D219-D227},

publisher = {Oxford University Press},

abstract = {© The Author(s) 2016.The Database of Protein Disorder (DisProt, URL: www.disprot.org) has been significantly updated and upgraded since its last major renewal in 2007. The current release holds information on more than 800 entries of IDPs/IDRs, i.e. intrinsically disordered proteins or regions that exist and function without a well-defined three-dimensional structure. We have re-curated previous entries to purge DisProt from conflicting cases, and also upgraded the functional classification scheme to reflect continuous advance in the field in the past 10 years or so. We define IDPs as proteins that are disordered along their entire sequence, i.e. entirely lack structural elements, and IDRs as regions that are at least five consecutive residues without well-defined structure. We base our assessment of disorder strictly on experimental evidence, such as X-ray crystallography and nuclear magnetic resonance (primary techniques) and a broad range of other experimental approaches (secondary techniques). Confident and ambiguous annotations are highlighted separately. DisProt 7.0 presents classified knowledge regarding the experimental characterization and functional annotations of IDPs/IDRs, and is intended to provide an invaluable resource for the research community for a better understanding structural disorder and for developing better computational tools for studying disordered proteins.},

note = {Cited by: 214; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84995948500,

title = {Mapping pathogenic mutations suggests an innovative structural model for the pendrin (SLC26A4) transmembrane domain},

author = {Claudio Bassot and Giovanni Minervini and Emanuela Leonardi and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84995948500&origin=inward},

doi = {10.1016/j.biochi.2016.10.002},

year  = {2017},

date = {2017-01-01},

journal = {Biochimie},

volume = {132},

pages = {109-120},

publisher = {Elsevier B.V.},

abstract = {© 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)Human pendrin (SLC26A4) is an anion transporter mostly expressed in the inner ear, thyroid and kidney. SLC26A4 gene mutations are associated with a broad phenotypic spectrum, including Pendred Syndrome and non-syndromic hearing loss with enlarged vestibular aqueduct (ns-EVA). No experimental structure of pendrin is currently available, making phenotype-genotype correlations difficult as predictions of transmembrane (TM) segments vary in number. Here, we propose a novel three-dimensional (3D) pendrin transmembrane domain model based on the SLC26Dg transporter. The resulting 14 TM topology was found to include two non-canonical transmembrane segments crucial for pendrin activity. Mutation mapping of 147 clinically validated pathological mutations shows that most affect two previously undescribed TM regions.},

note = {Cited by: 21},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85026471401,

title = {Dynamic scaffolds for neuronal signaling: In silico analysis of the TANC protein family},

author = {Alessandra Gasparini and Silvio C. E. Tosatto and Alessandra Murgia and Emanuela Leonardi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85026471401&origin=inward},

doi = {10.1038/s41598-017-05748-5},

year  = {2017},

date = {2017-01-01},

journal = {Scientific Reports},

volume = {7},

number = {1},

publisher = {Nature Publishing GroupHoundmillsBasingstoke, HampshireRG21 6XS},

abstract = {© 2017 The Author(s).The emergence of genes implicated across multiple comorbid neurologic disorders allows to identify shared underlying molecular pathways. Recently, investigation of patients with diverse neurologic disorders found TANC1 and TANC2 as possible candidate disease genes. While the TANC proteins have been reported as postsynaptic scaffolds influencing synaptic spines and excitatory synapse strength, their molecular functions remain unknown. Here, we conducted a comprehensive in silico analysis of the TANC protein family to characterize their molecular role and understand possible neurobiological consequences of their disruption. The known Ankyrin and tetratricopeptide repeat (TPR) domains have been modeled. The newly predicted N-terminal ATPase domain may function as a regulated molecular switch for downstream signaling. Several putative conserved protein binding motifs allowed to extend the TANC interaction network. Interestingly, we highlighted connections with different signaling pathways converging to modulate neuronal activity. Beyond a known role for TANC family members in the glutamate receptor pathway, they seem linked to planar cell polarity signaling, Hippo pathway, and cilium assembly. This suggests an important role in neuron projection, extension and differentiation.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85016144082,

title = {RepeatsDB 2.0: Improved annotation, classification, search and visualization of repeat protein structures},

author = {Lisanna Paladin and Layla Hirsh and Damiano Piovesan and Miguel A. Andrade-Navarro and Andrey V. Kajava and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85016144082&origin=inward},

doi = {10.1093/nar/gkw1136},

year  = {2017},

date = {2017-01-01},

journal = {Nucleic Acids Research},

volume = {45},

number = {D1},

pages = {D308-D312},

publisher = {Oxford University Press},

abstract = {© 2016 The Author(s).RepeatsDB 2.0 (URL: http://repeatsdb.bio.unipd.it/) is an update of the database of annotated tandem repeat protein structures. Repeat proteins are a widespread class of non-globular proteins carrying heterogeneous functions involved in several diseases. Here we provide a new version of RepeatsDB with an improved classification schema including high quality annotations for ∼5400 protein structures. RepeatsDB 2.0 features information on start and end positions for the repeat regions and units for all entries. The extensive growth of repeat unit characterization was possible by applying the novel ReUPred annotation method over the entire Protein Data Bank, with data quality is guaranteed by an extensive manual validation for >60% of the entries. The updated web interface includes a new search engine for complex queries and a fully re-designed entry page for a better overview of structural data. It is now possible to compare unit positions, together with secondary structure, fold information and Pfam domains. Moreover, a new classification level has been introduced on top of the existing scheme as an independent layer for sequence similarity relationships at 40%, 60% and 90% identity.},

note = {Cited by: 25; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85019446021,

title = {Ca2+ binding to F-ATP synthase β subunit triggers the mitochondrial permeability transition},

author = {Valentina Giorgio and Victoria Burchell and Marco Schiavone and Claudio Bassot and Giovanni Minervini and Valeria Petronilli and Francesco Argenton and Michael Forte and Silvio Tosatto and Giovanna Lippe and Paolo Bernardi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85019446021&origin=inward},

doi = {10.15252/embr.201643354},

year  = {2017},

date = {2017-01-01},

journal = {EMBO Reports},

volume = {18},

number = {7},

pages = {1065-1076},

publisher = {Wiley-VCH Verlaginfo@wiley-vch.de},

abstract = {© 2017 The AuthorsF-ATP synthases convert the electrochemical energy of the H+ gradient into the chemical energy of ATP with remarkable efficiency. Mitochondrial F-ATP synthases can also undergo a Ca2+-dependent transformation to form channels with properties matching those of the permeability transition pore (PTP), a key player in cell death. The Ca2+ binding site and the mechanism(s) through which Ca2+ can transform the energy-conserving enzyme into a dissipative structure promoting cell death remain unknown. Through in vitro, in vivo and in silico studies we (i) pinpoint the “Ca2+-trigger site” of the PTP to the catalytic site of the F-ATP synthase β subunit and (ii) define a conformational change that propagates from the catalytic site through OSCP and the lateral stalk to the inner membrane. T163S mutants of the β subunit, which show a selective decrease in Ca2+-ATP hydrolysis, confer resistance to Ca2+-induced, PTP-dependent death in cells and developing zebrafish embryos. These findings are a major advance in the molecular definition of the transition of F-ATP synthase to a channel and of its role in cell death.},

note = {Cited by: 194; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85016091177,

title = {Simultaneous quantification of protein order and disorder},

author = {Pietro Sormanni and Damiano Piovesan and Gabriella T. Heller and Massimiliano Bonomi and Predrag Kukic and Carlo Camilloni and Monika Fuxreiter and Zsuzsanna Dosztanyi and Rohit V Pappu and M Madan Babu and Sonia Longhi and Peter Tompa and A Keith Dunker and Vladimir N Uversky and Silvio C E Tosatto and Michele Vendruscolo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85016091177&origin=inward},

doi = {10.1038/nchembio.2331},

year  = {2017},

date = {2017-01-01},

journal = {Nature Chemical Biology},

volume = {13},

number = {4},

pages = {339-342},

publisher = {Nature Publishing GroupHoundmillsBasingstoke, HampshireRG21 6XS},

note = {Cited by: 105; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85019402721,

title = {Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI},

author = {Marco Carraro and Giovanni Minervini and Manuel Giollo and Yana Bromberg and Emidio Capriotti and Rita Casadio and Roland Dunbrack and Lisa Elefanti and Pietro Fariselli and Carlo Ferrari and Julian Gough and Panagiotis Katsonis and Emanuela Leonardi and Olivier Lichtarge and Chiara Menin and Pier Luigi Martelli and Abhishek Niroula and Lipika R. Pal and Susanna Repo and Maria Chiara Scaini and Mauno Vihinen and Qiong Wei and Qifang Xu and Yuedong Yang and Yizhou Yin and Jan Zaucha and Huiying Zhao and Yaoqi Zhou and Steven E. Brenner and John Moult and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85019402721&origin=inward},

doi = {10.1002/humu.23235},

year  = {2017},

date = {2017-01-01},

journal = {Human Mutation},

volume = {38},

number = {9},

pages = {1042-1050},

publisher = {John Wiley and Sons Inc},

abstract = {© 2017 Wiley Periodicals, Inc.Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype–phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of 10 variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene. Twenty-two pathogenicity predictors were assessed with a variety of accuracy measures for reliability in a medical context. Different assessment measures were combined in an overall ranking to provide more robust results. The R scripts used for assessment are publicly available from a GitHub repository for future use in similar assessment exercises. Despite a limited test-set size, our findings show a variety of results, with some methods performing significantly better. Methods combining different strategies frequently outperform simpler approaches. The best predictor, Yang&Zhou lab, uses a machine learning method combining an empirical energy function measuring protein stability with an evolutionary conservation term. The p16INK4a challenge highlights how subtle structural effects can neutralize otherwise deleterious variants.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85027511944,

title = {Crohn disease risk prediction—Best practices and pitfalls with exome data},

author = {Manuel Giollo and David T. Jones and Marco Carraro and Emanuela Leonardi and Carlo Ferrari and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85027511944&origin=inward},

doi = {10.1002/humu.23177},

year  = {2017},

date = {2017-01-01},

journal = {Human Mutation},

volume = {38},

number = {9},

pages = {1193-1200},

publisher = {John Wiley and Sons Inc.P.O.Box 18667NewarkNJ 07191-8667},

abstract = {© 2017 Wiley Periodicals, Inc.The Critical Assessment of Genome Interpretation (CAGI) experiment is the first attempt to evaluate the state-of-the-art in genetic data interpretation. Among the proposed challenges, Crohn disease (CD) risk prediction has become the most classic problem spanning three editions. The scientific question is very hard: can anybody assess the risk to develop CD given the exome data alone? This is one of the ultimate goals of genetic analysis, which motivated most CAGI participants to look for powerful new methods. In the 2016 CD challenge, we implemented all the best methods proposed in the past editions. This resulted in 10 algorithms, which were evaluated fairly by CAGI organizers. We also used all the data available from CAGI 11 and 13 to maximize the amount of training samples. The most effective algorithms used known genes associated with CD from the literature. No method could evaluate effectively the importance of unannotated variants by using heuristics. As a downside, all CD datasets were strongly affected by sample stratification. This affected the performance reported by assessors. Therefore, we expect that future datasets will be normalized in order to remove population effects. This will improve methods comparison and promote algorithms focused on causal variants discovery.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85014243730,

title = {Conformational diversity analysis reveals three functional mechanisms in proteins},

author = {Alexander Miguel Monzon and Diego Javier Zea and María Silvina Fornasari and Tadeo E. Saldaño and Sebastian Fernandez-Alberti and Silvio C. E. Tosatto and Gustavo Parisi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85014243730&origin=inward},

doi = {10.1371/journal.pcbi.1005398},

year  = {2017},

date = {2017-01-01},

journal = {PLoS Computational Biology},

volume = {13},

number = {2},

publisher = {Public Library of Science},

abstract = {© 2017 Monzon et al.Protein motions are a key feature to understand biological function. Recently, a large-scale analysis of protein conformational diversity showed a positively skewed distribution with a peak at 0.5 Å C-alpha root-mean-square-deviation (RMSD). To understand this distribution in terms of structure-function relationships, we studied a well curated and large dataset of textasciitilde 5,000 proteins with experimentally determined conformational diversity. We searched for global behaviour patterns studying how structure-based features change among the available conformer population for each protein. This procedure allowed us to describe the RMSD distribution in terms of three main protein classes sharing given properties. The largest of these protein subsets (textasciitilde 60%), which we call “rigid” (average RMSD = 0.83 Å), has no disordered regions, shows low conformational diversity, the largest tunnels and smaller and buried cavities. The two additional subsets contain disordered regions, but with differential sequence composition and behaviour. Partially disordered proteins have on average 67% of their conformers with disordered regions, average RMSD = 1.1 Å, the highest number of hinges and the longest disordered regions. In contrast, malleable proteins have on average only 25% of disordered conformers and average RMSD = 1.3 Å, flexible cavities affected in size by the presence of disordered regions and show the highest diversity of cognate ligands. Proteins in each set are mostly non-homologous to each other, share no given fold class, nor functional similarity but do share features derived from their conformer population. These shared features could represent conformational mechanisms related with biological functions.},

note = {Cited by: 45; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85032200484,

title = {Homology modeling in a dynamical world},

author = {Alexander Miguel Monzon and Diego Javier Zea and Cristina Marino-Buslje and Gustavo Parisi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85032200484&origin=inward},

doi = {10.1002/pro.3274},

year  = {2017},

date = {2017-01-01},

journal = {Protein Science},

volume = {26},

number = {11},

pages = {2195-2206},

publisher = {Blackwell Publishing Ltdcustomerservices@oxonblackwellpublishing.com},

abstract = {© 2017 The Protein SocietyA key concept in template-based modeling (TBM) is the high correlation between sequence and structural divergence, with the practical consequence that homologous proteins that are similar at the sequence level will also be similar at the structural level. However, conformational diversity of the native state will reduce the correlation between structural and sequence divergence, because structural variation can appear without sequence diversity. In this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We find that the extent of conformational diversity can be as high as the maximum structural divergence among families. Also, as expected, conformational diversity impairs the well-established correlation between sequence and structural divergence, which is nosier than previously suggested. However, we found that this noise can be resolved using a priori information coming from the structure-function relationship. We show that protein families with low conformational diversity show a well-correlated relationship between sequence and structural divergence, which is severely reduced in proteins with larger conformational diversity. This lack of correlation could impair TBM results in highly dynamical proteins. Finally, we also find that the presence of order/disorder can provide useful beforehand information for better TBM performance.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85020488911,

title = {Matching phenotypes to whole genomes: Lessons learned from four iterations of the personal genome project community challenges},

author = {Binghuang Cai and Biao Li and Nikki Kiga and Janita Thusberg and Timothy Bergquist and Yun-Ching Chen and Noushin Niknafs and Hannah Carter and Collin Tokheim and Violeta Beleva-Guthrie and Christopher Douville and Rohit Bhattacharya and Hui Ting Grace Yeo and Jean Fan and Sohini Sengupta and Dewey Kim and Melissa Cline and Tychele Turner and Mark Diekhans and Jan Zaucha and Lipika R. Pal and Chen Cao and Chen-Hsin Yu and Yizhou Yin and Marco Carraro and Manuel Giollo and Carlo Ferrari and Emanuela Leonardi and Silvio C. E. Tosatto and Jason Bobe and Madeleine Ball and Roger A. Hoskins and Susanna Repo and George Church and Steven E. Brenner and John Moult and Julian Gough and Mario Stanke and Rachel Karchin and Sean D. Mooney},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85020488911&origin=inward},

doi = {10.1002/humu.23265},

year  = {2017},

date = {2017-01-01},

journal = {Human Mutation},

volume = {38},

number = {9},

pages = {1266-1276},

publisher = {John Wiley and Sons Inc},

abstract = {© 2017 Wiley Periodicals, Inc.The advent of next-generation sequencing has dramatically decreased the cost for whole-genome sequencing and increased the viability for its application in research and clinical care. The Personal Genome Project (PGP) provides unrestricted access to genomes of individuals and their associated phenotypes. This resource enabled the Critical Assessment of Genome Interpretation (CAGI) to create a community challenge to assess the bioinformatics community's ability to predict traits from whole genomes. In the CAGI PGP challenge, researchers were asked to predict whether an individual had a particular trait or profile based on their whole genome. Several approaches were used to assess submissions, including ROC AUC (area under receiver operating characteristic curve), probability rankings, the number of correct predictions, and statistical significance simulations. Overall, we found that prediction of individual traits is difficult, relying on a strong knowledge of trait frequency within the general population, whereas matching genomes to trait profiles relies heavily upon a small number of common traits including ancestry, blood type, and eye color. When a rare genetic disorder is present, profiles can be matched when one or more pathogenic variants are identified. Prediction accuracy has improved substantially over the last 6 years due to improved methodology and a better understanding of features.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85039065468,

title = {Novel interactions of the von Hippel-Lindau (pVHL) tumor suppressor with the CDKN1 family of cell cycle inhibitors},

author = {Giovanni Minervini and Raffaele Lopreiato and Raissa Bortolotto and Antonella Falconieri and Geppo Sartori and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85039065468&origin=inward},

doi = {10.1038/srep46562},

year  = {2017},

date = {2017-01-01},

journal = {Scientific Reports},

volume = {7},

publisher = {Nature Publishing GroupHoundmillsBasingstoke, HampshireRG21 6XS},

abstract = {© The Author(s) 2017.Germline inactivation of the von Hippel-Lindau (VHL) tumor suppressor predisposes patients to develop different highly vascularized cancers. pVHL targets the hypoxia-inducible transcription factor (HIF-1α) for degradation, modulating the activation of various genes involved in hypoxia response. Hypoxia plays a relevant role in regulating cell cycle progression, inducing growth arrest in cells exposed to prolonged oxygen deprivation. However, the exact molecular details driving this transition are far from understood. Here, we present novel interactions between pVHL and the cyclin-dependent kinase inhibitor family CDKN1 (p21, p27 and p57). Bioinformatics analysis, yeast two-hybrid screening and co-immunoprecipitation assays were used to predict, dissect and validate the interactions. We found that the CDKN1 proteins share a conserved region mimicking the HIF-1α motif responsible for pVHL binding. Intriguingly, a p27 site-specific mutation associated to cancer is shown to modulate this novel interaction. Our findings suggest a new connection between the pathways regulating hypoxia and cell cycle progression.},

note = {Cited by: 7; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85022033200,

title = {Working toward precision medicine: Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges},

author = {Roxana Daneshjou and Yanran Wang and Yana Bromberg and Samuele Bovo and Pier L Martelli and Giulia Babbi and Pietro Di Lena and Rita Casadio and Matthew Edwards and David Gifford and David T Jones and Laksshman Sundaram and Rajendra Rana Bhat and Xiaolin Li and Lipika R. Pal and Kunal Kundu and Yizhou Yin and John Moult and Yuxiang Jiang and Vikas Pejaver and Kymberleigh A. Pagel and Biao Li and Sean D. Mooney and Predrag Radivojac and Sohela Shah and Marco Carraro and Alessandra Gasparini and Emanuela Leonardi and Manuel Giollo and Carlo Ferrari and Silvio C E Tosatto and Eran Bachar and Johnathan R. Azaria and Yanay Ofran and Ron Unger and Abhishek Niroula and Mauno Vihinen and Billy Chang and Maggie H Wang and Andre Franke and Britt-Sabina Petersen and Mehdi Pirooznia and Peter Zandi and Richard McCombie and James B. Potash and Russ B. Altman and Teri E. Klein and Roger A. Hoskins and Susanna Repo and Steven E. Brenner and Alexander A. Morgan},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85022033200&origin=inward},

doi = {10.1002/humu.23280},

year  = {2017},

date = {2017-01-01},

journal = {Human Mutation},

volume = {38},

number = {9},

pages = {1182-1192},

publisher = {John Wiley and Sons Inc},

abstract = {© 2017 Wiley Periodicals, Inc.Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype–phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype–phenotype relationships.},

note = {Cited by: 39; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84953293603,

title = {Downregulation of GABAA Receptor Recycling Mediated by HAP1 Contributes to Neuronal Death in In Vitro Brain Ischemia},

author = {Miranda Mele and Maria Cristina Aspromonte and Carlos B. Duarte},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84953293603&origin=inward},

doi = {10.1007/s12035-015-9661-9},

year  = {2017},

date = {2017-01-01},

journal = {Molecular Neurobiology},

volume = {54},

number = {1},

pages = {45-57},

publisher = {Humana Press Inc.humana@humanapr.com},

abstract = {© 2016, Springer Science+Business Media New York.Downregulation of GABAergic synaptic transmission contributes to the increase in overall excitatory activity in the ischemic brain. A reduction of GABAA receptor (GABAAR) surface expression partly accounts for this decrease in inhibitory activity, but the mechanisms involved are not fully elucidated. In this work, we investigated the alterations in GABAAR trafficking in cultured rat hippocampal neurons subjected to oxygen/glucose deprivation (OGD), an in vitro model of global brain ischemia, and their impact in neuronal death. The traffic of GABAAR was evaluated after transfection of hippocampal neurons with myc-tagged GABAAR β3 subunits. OGD decreased the rate of GABAAR β3 subunit recycling and reduced the interaction of the receptors with HAP1, a protein involved in the recycling of the receptors. Furthermore, OGD induced a calpain-mediated cleavage of HAP1. Transfection of hippocampal neurons with HAP1A or HAP1B isoforms reduced the OGD-induced decrease in surface expression of GABAAR β3 subunits, and HAP1A maintained the rate of receptor recycling. Furthermore, transfection of hippocampal neurons with HAP1 significantly decreased OGD-induced cell death. These results show a key role for HAP1 protein in the downmodulation of GABAergic neurotransmission during cerebral ischemia, which contributes to neuronal demise.},

note = {Cited by: 24},

keywords = {},

pubstate = {published},

tppubtype = {article}

}