@article{SCOPUS_ID:85087320561,

title = {PlaToLoCo: The first web meta-server for visualization and annotation of low complexity regions in proteins},

author = {Patryk Jarnot and Joanna Ziemska-Legiecka and Laszlo Dobson and Matthew Merski and Pablo Mier and Miguel A. Andrade-Navarro and John M. Hancock and Zsuzsanna Dosztányi and Lisanna Paladin and Marco Necci and Damiano Piovesan and Silvio C. E. Tosatto and Vasilis J. Promponas and Marcin Grynberg and Aleksandra Gruca},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85087320561&origin=inward},

doi = {10.1093/NAR/GKAA339},

year  = {2020},

date = {2020-01-01},

journal = {Nucleic Acids Research},

volume = {48},

number = {W1},

pages = {W77-W84},

publisher = {Oxford University Press},

abstract = {© 2020 Oxford University Press. All rights reserved.Low complexity regions (LCRs) in protein sequences are characterized by a less diverse amino acid composition compared to typically observed sequence diversity. Recent studies have shown that LCRs may co-occur with intrinsically disordered regions, are highly conserved in many organisms, and often play important roles in protein functions and in diseases. In previous decades, several methods have been developed to identify regions with LCRs or amino acid bias, but most of them as stand-alone applications and currently there is no web-based tool which allows users to explore LCRs in protein sequences with additional functional annotations. We aim to fill this gap by providing PlaToLoCo-PLAtform of TOols for LOw COmplexity-a meta-server that integrates and collects the output of five different state-of-theart tools for discovering LCRs and provides functional annotations such as domain detection, transmembrane segment prediction, and calculation of amino acid frequencies. In addition, the union or intersection of the results of the search on a query sequence can be obtained. By developing the Pla-ToLoCo meta-server, we provide the community with a fast and easily accessible tool for the analysis of LCRs with additional information included to aid the interpretation of the results. The PlaToLoCo platform is available at: Http://platoloco.aei.polsl.pl/.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85090971828,

title = {A novel approach to investigate the evolution of structured tandem repeat protein families by exon duplication},

author = {Lisanna Paladin and Marco Necci and Damiano Piovesan and Pablo Mier and Miguel A. Andrade-Navarro and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85090971828&origin=inward},

doi = {10.1016/j.jsb.2020.107608},

year  = {2020},

date = {2020-01-01},

journal = {Journal of Structural Biology},

volume = {212},

number = {2},

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

abstract = {© 2020 Elsevier Inc.Tandem Repeat Proteins (TRPs) are ubiquitous in cells and are enriched in eukaryotes. They contributed to the evolution of organism complexity, specializing for functions that require quick adaptability such as immunity-related functions. To investigate the hypothesis of repeat protein evolution through exon duplication and rearrangement, we designed a tool to analyze the relationships between exon/intron patterns and structural symmetries. The tool allows comparison of the structure fragments as defined by exon/intron boundaries from Ensembl against the structural element repetitions from RepeatsDB. The all-against-all pairwise structural alignment between fragments and comparison of the two definitions (structural units and exons) are visualized in a single matrix, the “repeat/exon plot”. An analysis of different repeat protein families, including the solenoids Leucine-Rich, Ankyrin, Pumilio, HEAT repeats and the β propellers Kelch-like, WD40 and RCC1, shows different behaviors, illustrated here through examples. For each example, the analysis of the exon mapping in homologous proteins supports the conservation of their exon patterns. We propose that when a clear-cut relationship between exon and structural boundaries can be identified, it is possible to infer a specific “evolutionary pattern” which may improve TRPs detection and classification.},

note = {Cited by: 10},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85083902829,

title = {Novel Missense Variant in MYL2 Gene Associated with Hypertrophic Cardiomyopathy Showing High Incidence of Restrictive Physiology},

author = {Marzia De Bortoli and Riccardo Vio and Cristina Basso and Martina Calore and Giovanni Minervini and Annalisa Angelini and Paola Melacini and Libero Vitiello and Giovanni Vazza and Gaetano Thiene and Silvio Tosatto and Domenico Corrado and Sabino Iliceto and Alessandra Rampazzo and Chiara Calore},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85083902829&origin=inward},

doi = {10.1161/CIRCGEN.119.002824},

year  = {2020},

date = {2020-01-01},

journal = {Circulation: Genomic and Precision Medicine},

volume = {13},

number = {4},

publisher = {Lippincott Williams and Wilkins},

note = {Cited by: 16},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85087390580,

title = {The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer},

author = {Giovanni Minervini and Maria Pennuto and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85087390580&origin=inward},

doi = {10.1098/rsob.200109},

year  = {2020},

date = {2020-01-01},

journal = {Open Biology},

volume = {10},

number = {7},

publisher = {Royal Society Publishing},

abstract = {© 2020 The Authors.The von Hippel-Lindau protein (pVHL) is a tumour suppressor mainly known for its role as master regulator of hypoxia-inducible factor (HIF) activity. Functional inactivation of pVHL is causative of the von Hippel-Lindau disease, an inherited predisposition to develop different cancers. Due to its impact on human health, pVHL has been widely studied in the last few decades. However, investigations mostly focus on its role in degrading HIFs, whereas alternative pVHL protein-protein interactions and functions are insistently surfacing in the literature. In this review, we analyse these almost neglected functions by dissecting specific conditions in which pVHL is proposed to have differential roles in promoting cancer. We reviewed its role in regulating phosphorylation as a number of works suggest pVHL to act as an inhibitor by either degrading or promoting downregulation of specific kinases. Further, we summarize hypoxia-dependent and -independent pVHL interactions with multiple protein partners and discuss their implications in tumorigenesis.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85089246670,

title = {Clinical and molecular description of 19 patients with GATAD2B-Associated Neurodevelopmental Disorder (GAND)},

author = {Gabriella Vera and Arthur Sorlin and Geoffroy Delplancq and François Lecoquierre and Marie Brasseur-Daudruy and Florence Petit and Thomas Smol and Alban Ziegler and Dominique Bonneau and Estelle Colin and Sandra Mercier and Benjamin Cogné and Stéphane Bézieau and Patrick Edery and Gaetan Lesca and Nicolas Chatron and Isabelle Sabatier and Bénédicte Duban-Bedu and Cindy Colson and Amélie Piton and Benjamin Durand and Yline Capri and Laurence Perrin and Antje Wiesener and Christiane Zweier and Reza Maroofian and Christopher J. Carroll and Hamid Galehdari and Neda Mazaheri and Bert Callewaert and Fabienne Giulianno and Khaoula Zaafrane-Khachnaoui and Rebecca Buchert-Lo and Tobias Haack and Janine Magg and Angelika Rieß and Maria Blandfort and Stephan Waldmüller and Veronka Horber and Emanuela Leonardi and Roberta Polli and Licia Turolla and Alessandra Murgia and Thierry Frebourg and Anne Sophie Lebre and Gaël Nicolas and Pascale Saugier-Veber and Anne-Marie Guerrot},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85089246670&origin=inward},

doi = {10.1016/j.ejmg.2020.104004},

year  = {2020},

date = {2020-01-01},

journal = {European Journal of Medical Genetics},

volume = {63},

number = {10},

publisher = {Elsevier Masson SAS62 rue Camille DesmoulinsIssy les Moulineaux Cedex92442},

abstract = {© 2020De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management.},

note = {Cited by: 10; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85087532447,

title = {Assessing predictors for new post translational modification sites: A case study on hydroxylation},

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

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85087532447&origin=inward},

doi = {10.1371/journal.pcbi.1007967},

year  = {2020},

date = {2020-01-01},

journal = {PLoS Computational Biology},

volume = {16},

number = {6},

publisher = {Public Library of Science},

abstract = {Copyright: © 2020 Piovesan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Post-translational modification (PTM) sites have become popular for predictor development. However, with the exception of phosphorylation and a handful of other examples, PTMs suffer from a limited number of available training examples and sparsity in protein sequences. Here, proline hydroxylation is taken as an example to compare different methods and evaluate their performance on new experimentally determined sites. As a guide for effective experimental design, predictors require both high specificity and sensitivity. However, the self-reported performance may often not be indicative of prediction quality and detection of new sites is not guaranteed. We have benchmarked seven published hydroxylation site predictors on two newly constructed independent datasets. The self-reported performance is found to widely overestimate the real accuracy measured on independent datasets. No predictor performs better than random on new examples, indicating the refined models do not sufficiently generalize to detect new sites. The number of false positives is high and precision low, in particular for non-collagen proteins whose motifs are not conserved. As hydroxylation site predictors do not generalize for new data, caution is advised when using PTM predictors in the absence of independent evaluations, in particular for highly specific sites involved in signalling.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85070436802,

title = {PhaSePro: The database of proteins driving liquid-liquid phase separation},

author = {Bálint Mészáros and Gábor Erdos and Beáta Szabó and Éva Schád and Ágnes Tantos and Rawan Abukhairan and Tamás Horváth and Nikoletta Murvai and Orsolya P. Kovács and Márton Kovács and Silvio C. E. Tosatto and Péter Tompa and Zsuzsanna Dosztányi and Rita Pancsa},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85070436802&origin=inward},

doi = {10.1093/nar/gkz848},

year  = {2020},

date = {2020-01-01},

journal = {Nucleic Acids Research},

volume = {48},

number = {D1},

pages = {D360-D367},

publisher = {Oxford University Press},

abstract = {© 2019 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.Membraneless organelles (MOs) are dynamic liquid condensates that host a variety of specific cellular processes, such as ribosome biogenesis or RNA degradation. MOs form through liquid-liquid phase separation (LLPS), a process that relies on multivalent weak interactions of the constituent proteins and other macromolecules. Since the first discoveries of certain proteins being able to drive LLPS, it emerged as a general mechanism for the effective organization of cellular space that is exploited in all kingdoms of life. While numerous experimental studies report novel cases, the computational identification of LLPS drivers is lagging behind, and many open questions remain about the sequence determinants, composition, regulation and biological relevance of the resulting condensates. Our limited ability to overcome these issues is largely due to the lack of a dedicated LLPS database. Therefore, here we introduce PhaSePro (https://phasepro.elte.hu), an openly accessible, comprehensive, manually curated database of experimentally validated LLPS driver proteins/protein regions. It not only provides a wealth of information on such systems, but improves the standardization of data by introducing novel LLPS-specific controlled vocabularies. PhaSePro can be accessed through an appealing, user-friendly interface and thus has definite potential to become the central resource in this dynamically developing field.},

note = {Cited by: 141; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85091666355,

title = {The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel–Lindau tumor suppressor},

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

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85091666355&origin=inward},

doi = {10.1038/s41598-020-72683-3},

year  = {2020},

date = {2020-01-01},

journal = {Scientific Reports},

volume = {10},

number = {1},

publisher = {Nature Researchsubscriptions@nature.com},

abstract = {© 2020, The Author(s).Mutations of the von Hippel–Lindau (pVHL) tumor suppressor are causative of a familiar predisposition to develop different types of cancer. pVHL is mainly known for its role in regulating hypoxia-inducible factor 1 α (HIF-1α) degradation, thus modulating the hypoxia response. There are different pVHL isoforms, including pVHL30 and pVHL19. However, little is known about isoform-specific functions and protein–protein interactions. Integrating in silico predictions with in vitro and in vivo assays, we describe a novel interaction between pVHL and mouse double minute 2 homolog (MDM2). We found that pVHL30, and not pVHL19, forms a complex with MDM2, and that the N-terminal acidic tail of pVHL30 is required for its association with MDM2. Further, we demonstrate that an intrinsically disordered region upstream of the tetramerization domain of MDM2 is responsible for its isoform-specific association with pVHL30. This region is highly conserved in higher mammals, including primates, similarly to what has been already shown for the N-terminal tail of pVHL30. Finally, we show that overexpression of pVHL30 and MDM2 together reduces cell metabolic activity and necrosis, suggesting a synergistic effect of these E3 ubiquitin ligases. Collectively, our data show an isoform-specific interaction of pVHL with MDM2, suggesting an interplay between these two E3 ubiquitin ligases.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85083811469,

title = {Disentangling the complexity of low complexity proteins},

author = {Pablo Mier and Lisanna Paladin and Stella Tamana and Sophia Petrosian and Borbála Hajdu-Soltész and Annika Urbanek and Aleksandra Gruca and Dariusz Plewczynski and Marcin Grynberg and Pau Bernadó and Zoltán Gáspári and Christos A. Ouzounis and Vasilis J. Promponas and Andrey V. Kajava and John M Hancock and Silvio C. E. Tosatto and Zsuzsanna Dosztanyi and Miguel A. Andrade-Navarro},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85083811469&origin=inward},

doi = {10.1093/bib/bbz007},

year  = {2020},

date = {2020-01-01},

journal = {Briefings in Bioinformatics},

volume = {21},

number = {2},

pages = {458-472},

publisher = {Oxford University Press},

abstract = {© 2019 The Author(s) 2019. Published by Oxford University Press.There are multiple definitions for low complexity regions (LCRs) in protein sequences, with all of them broadly considering LCRs as regions with fewer amino acid types compared to an average composition. Following this view, LCRs can also be defined as regions showing composition bias. In this critical review, we focus on the definition of sequence complexity of LCRs and their connection with structure. We present statistics and methodological approaches that measure low complexity (LC) and related sequence properties. Composition bias is often associated with LC and disorder, but repeats, while compositionally biased, might also induce ordered structures. We illustrate this dichotomy, and more generally the overlaps between different properties related to LCRs, using examples. We argue that statistical measures alone cannot capture all structural aspects of LCRs and recommend the combined usage of a variety of predictive tools and measurements. While the methodologies available to study LCRs are already very advanced, we foresee that a more comprehensive annotation of sequences in the databases will enable the improvement of predictions and a better understanding of the evolution and the connection between structure and function of LCRs. This will require the use of standards for the generation and exchange of data describing all aspects of LCRs. Short abstract: There are multiple definitions for low complexity regions (LCRs) in protein sequences. In this critical review, we focus on the definition of sequence complexity of LCRs and their connection with structure. We present statistics and methodological approaches that measure low complexity (LC) and related sequence properties. Composition bias is often associated with LC and disorder, but repeats, while compositionally biased, might also induce ordered structures. We illustrate this dichotomy, plus overlaps between different properties related to LCRs, using examples.},

note = {Cited by: 70; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85072037151,

title = {Global network of computational biology communities: ISCB's regional student groups breaking barriers .},

author = {Sayane Shome and R. Gonzalo Parra and Nazeefa Fatima and Alexander Miguel Monzon and Bart Cuypers and Yumna Moosa and Nilson Da Rocha Coimbra and Juliana Assis and Carla Giner-Delgado and Handan Melike Dönertaş and Yesid Cuesta-Astroz and Geetha Saarunya and Imane Allali and Shruti Gupta and Ambuj Srivastava and Manisha Kalsan and Catalina Valdivia and Gabriel J. Olguin-Orellana and Sofia Papadimitriou and Daniele Parisi and Nikolaj Pagh Kristensen and Leonor Rib and Marouen Ben Guebila and Eugen Bauer and Gaia Zaffaroni and Amel Bekkar and Efejiro Ashano and Lisanna Paladin and Marco Necci and Nicolás N. Moreyra and Martin Rydén and Jordan Villalobos-Solís and Nikolaos Papadopoulos and Candice Rafael and Tülay Karakulak and Yasin Kaya and Yvonne Gladbach and Sandeep Kumar Dhanda and Nikolina Šoštarić and Aishwarya Alex and Dan Deblasio and Farzana Rahman},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85072037151&origin=inward},

doi = {10.12688/f1000research.20408.1},

year  = {2019},

date = {2019-01-01},

journal = {F1000Research},

volume = {8},

publisher = {F1000 Research Ltd},

abstract = {© 2019 Shome S et al.Regional Student Groups (RSGs) of the International Society for Computational Biology Student Council (ISCB-SC) have been instrumental to connect computational biologists globally and to create more awareness about bioinformatics education. This article highlights the initiatives carried out by the RSGs both nationally and internationally to strengthen the present and future of the bioinformatics community. Moreover, we discuss the future directions the organization will take and the challenges to advance further in the ISCB-SC main mission: “Nurture the new generation of computational biologists”.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85068071818,

title = {Arg-8 of yeast subunit e contributes to the stability of F-ATP synthase dimers and to the generation of the full-conductance mitochondrial megachannel},

author = {Lishu Guo and Michela Carraro and Andrea Carrer and Giovanni Minervini and Andrea Urbani and Ionica Masgras and Silvio C. E. Tosatto and Ildikò Szabò and Paolo Bernardi and Giovanna Lippe},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85068071818&origin=inward},

doi = {10.1074/jbc.RA119.008775},

year  = {2019},

date = {2019-01-01},

journal = {Journal of Biological Chemistry},

volume = {294},

number = {28},

pages = {10987-10997},

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

abstract = {© 2019 Guo et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.The mitochondrial F-ATP synthase is a complex molecular motor arranged in V-shaped dimers that is responsible for most cellular ATP synthesis in aerobic conditions. In the yeast F-ATP synthase, subunits e and g of the FO sector constitute a lateral domain, which is required for dimer stability and cristae formation. Here, by using site-directed mutagenesis, we identified Arg-8 of subunit e as a critical residue in mediating interactions between subunits e and g, most likely through an interaction with Glu-83 of subunit g. Consistent with this hypothesis, (i) the substitution of Arg-8 in subunit e (eArg-8) with Ala or Glu or of Glu-83 in subunit g (gGlu-83) with Ala or Lys destabilized the digitonin-extracted F-ATP synthase, resulting in decreased dimer formation as revealed by blue-native electrophoresis; and (ii) simultaneous substitution of eArg-8 with Glu and of gGlu-83 with Lys rescued digitonin-stable F-ATP synthase dimers. When tested in lipid bilayers for generation of Ca2-dependent channels, WT dimers displayed the high-conductance channel activity expected for the mitochondrial megachannel/permeability transition pore, whereas dimers obtained at low digitonin concentrations from the Arg-8 variants displayed currents of strikingly small conductance. Remarkably, double replacement of eArg-8 with Glu and of gGlu-83 with Lys restored high-conductance channels indistinguishable from those seen in WT enzymes. These findings suggest that the interaction of subunit e with subunit g is important for generation of the full-conductance megachannel from F-ATP synthase.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85054737969,

title = {On the dynamical incompleteness of the Protein Data Bank},

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

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85054737969&origin=inward},

doi = {10.1093/bib/bbx084},

year  = {2019},

date = {2019-01-01},

journal = {Briefings in Bioinformatics},

volume = {20},

number = {1},

pages = {356-359},

publisher = {Oxford University Press},

abstract = {© The Author 2017. Published by Oxford University Press. All rights reserved.Major scientific challenges that are beyond the capability of individuals need to be addressed by multi-disciplinary and multi-institutional consortia. Examples of these endeavours include the Human Genome Project, and more recently, the Structural Genomics (SG) initiative. The SG initiative pursues the expansion of structural coverage to include at least one structural representative for each protein family to derive the remaining structures using homology modelling. However, biological function is inherently connected with protein dynamics that can be studied by knowing different structures of the same protein. This ensemble of structures provides snapshots of protein conformational diversity under native conditions. Thus, sequence redundancy in the Protein Data Bank (PDB) (i.e. crystallization of the same protein under different conditions) is therefore an essential input contributing to experimentally based studies of protein dynamics and providing insights into protein function. In this work, we show that sequence redundancy, a key concept for exploring protein dynamics, is highly biased and fundamentally incomplete in the PDB. Additionally, our results show that dynamical behaviour of proteins cannot be inferred using homologous proteins. Minor to moderate changes in sequence can produce great differences in dynamical behaviour. Nonetheless, the structural and dynamical incompleteness of the PDB is apparently unrelated concepts in SG. While the first could be reversed by promoting the extension of the structural coverage, we would like to emphasize that further focused efforts will be needed to amend the incompleteness of the PDB in terms of dynamical information content, essential to fully understand protein function.},

note = {Cited by: 11},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85061758137,

title = {Ensembles from Ordered and Disordered Proteins Reveal Similar Structural Constraints during Evolution},

author = {Julia Marchetti and Alexander Miguel Monzon and Silvio C. E. Tosatto and Gustavo Parisi and María Silvina Fornasari},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85061758137&origin=inward},

doi = {10.1016/j.jmb.2019.01.031},

year  = {2019},

date = {2019-01-01},

journal = {Journal of Molecular Biology},

volume = {431},

number = {6},

pages = {1298-1307},

publisher = {Academic Press},

abstract = {© 2019 Elsevier LtdThe conformations accessible to proteins are determined by the inter-residue interactions between amino acid residues. During evolution, structural constraints that are required for protein function providing biologically relevant information can exist. Here, we studied the proportion of sites evolving under structural constraints in two very different types of ensembles, those coming from ordered and disordered proteins. Using a structurally constrained model of protein evolution, we found that both types of ensembles show comparable, near 40%, number of positions evolving under structural constraints. Among these sites, textasciitilde 68% are in disordered regions and textasciitilde 57% of them show long-range inter-residue contacts. Also, we found that disordered ensembles are redundant in reference to their structurally constrained evolutionary information and could be described on average with textasciitilde 11 conformers. Despite the different complexity of the studied ensembles and proteins, the similar constraints reveal a comparable level of selective pressure to maintain their biological functions. These results highlight the importance of the evolutionary information to recover meaningful biological information to further characterize conformational ensembles.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85060061940,

title = {Nurturing tomorrow’s leaders: The ISCB student council symposia in 2018 .},

author = {Daniele Parisi and Gabriel J. Olguín-Orellana and Eli J. Draizen and Nilson Da Rocha Coimbra and Nikolaos Papadopoulos and Susanne Kirchen and Yvonne Saara Gladbach and Numrah Fadra and Nazeefa Fatima and Aishwarya Alex Namasivayam and Sayane Shome and Dan Deblasio and Alexander M. Monzon and Farzana Rahman and R. Gonzalo Parra},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85060061940&origin=inward},

doi = {10.12688/f1000research.17739.1},

year  = {2019},

date = {2019-01-01},

journal = {F1000Research},

volume = {8},

publisher = {F1000 Research Ltd},

abstract = {© 2019 Parisi D et al.The Student Council of the International Society for Computational Biology (ISCB-SC) is a student-focused organization for researchers from all early career levels of training (undergraduates, masters, PhDs and postdocs) that organizes bioinformatics and computational biology activities across the globe. Among its activities, the ISCB-SC organizes several symposia in different continents, many times, with the help of the Regional Student Groups (RSGs) that are based on each region. In this editorial we highlight various key moments and learned lessons from the 14th Student Council Symposium (SCS, Chicago, USA), the 5th European Student Council Symposium (ESCS, Athens, Greece) and the 3rd Latin American Student Council Symposium (LA-SCS, Viña del Mar, Chile).},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85059346502,

title = {A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in the TP63 gene in patients with arrhythmogenic cardiomyopathy},

author = {Giulia Poloni and Martina Calore and Ilaria Rigato and Elena Marras and Giovanni Minervini and Elisa Mazzotti and Alessandra Lorenzon and Ilena Egle Astrid Li Mura and Andrea Telatin and Ivano Zara and Barbara Simionati and Martina Perazzolo Marra and Jessica Ponti and Gianluca Occhi and Libero Vitiello and Luciano Daliento and Gaetano Thiene and Cristina Basso and Domenico Corrado and Silvio Tosatto and Barbara Bauce and Alessandra Rampazzo and Marzia De Bortoli},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85059346502&origin=inward},

doi = {10.1016/j.hrthm.2018.11.015},

year  = {2019},

date = {2019-01-01},

journal = {Heart Rhythm},

volume = {16},

number = {5},

pages = {773-780},

publisher = {Elsevier B.V.},

abstract = {© 2018 Heart Rhythm SocietyBackground: Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for ∼60% of ACM cases, but the remaining 40% is still genetically elusive. Objective: The purpose of this study was to identify the underlying genetic cause in probands with ACM. Methods: DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes—DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes. Results: About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed ≥1 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency. Conclusion: Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined.},

note = {Cited by: 13},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85068874641,

title = {Network analysis of dynamically important residues in protein structures mediating ligand-binding conformational changes},

author = {Tadeo E. Saldaño and Silvio C. E. Tosatto and Gustavo Parisi and Sebastian Fernandez-Alberti},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85068874641&origin=inward},

doi = {10.1007/s00249-019-01384-1},

year  = {2019},

date = {2019-01-01},

journal = {European Biophysics Journal},

volume = {48},

number = {6},

pages = {559-568},

publisher = {Springer Verlagservice@springer.de},

abstract = {© 2019, European Biophysical Societies' Association.According to the generalized conformational selection model, ligand binding involves the co-existence of at least two conformers with different ligand-affinities in a dynamical equilibrium. Conformational transitions between them should be guaranteed by intramolecular vibrational dynamics associated to each conformation. These motions are, therefore, related to the biological function of a protein. Positions whose mutations are found to alter these vibrations the most can be defined as key positions, that is, dynamically important residues that mediate the ligand-binding conformational change. In a previous study, we have shown that these positions are evolutionarily conserved. They correspond to buried aliphatic residues mostly localized in regular structured regions of the protein like β-sheets and α-helices. In the present paper, we perform a network analysis of these key positions for a large dataset of paired protein structures in the ligand-free and ligand-bound form. We observe that networks of interactions between these key positions present larger and more integrated networks with faster transmission of the information. Besides, networks of residues result that are robust to conformational changes. Our results reveal that the conformational diversity of proteins seems to be guaranteed by a network of strongly interconnected key positions rather than individual residues.},

note = {Cited by: 9},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85070520084,

title = {Performance of computational methods for the evaluation of pericentriolar material 1 missense variants in CAGI-5},

author = {Alexander Miguel Monzon and Marco Carraro and Luigi Chiricosta and Francesco Reggiani and James Han and Kivilcim Ozturk and Yanran Wang and Maximilian Miller and Yana Bromberg and Emidio Capriotti and Castrense Savojardo and Giulia Babbi and Pier L. Martelli and Rita Casadio and Panagiotis Katsonis and Olivier Lichtarge and Hannah Carter and Maria Kousi and Nicholas Katsanis and Gaia Andreoletti and John Moult and Steven E. Brenner and Carlo Ferrari and Emanuela Leonardi and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85070520084&origin=inward},

doi = {10.1002/humu.23856},

year  = {2019},

date = {2019-01-01},

journal = {Human Mutation},

volume = {40},

number = {9},

pages = {1474-1485},

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

abstract = {© 2019 Wiley Periodicals, Inc.The CAGI-5 pericentriolar material 1 (PCM1) challenge aimed to predict the effect of 38 transgenic human missense mutations in the PCM1 protein implicated in schizophrenia. Participants were provided with 16 benign variants (negative controls), 10 hypomorphic, and 12 loss of function variants. Six groups participated and were asked to predict the probability of effect and standard deviation associated to each mutation. Here, we present the challenge assessment. Prediction performance was evaluated using different measures to conclude in a final ranking which highlights the strengths and weaknesses of each group. The results show a great variety of predictions where some methods performed significantly better than others. Benign variants played an important role as negative controls, highlighting predictors biased to identify disease phenotypes. The best predictor, Bromberg lab, used a neural-network-based method able to discriminate between neutral and non-neutral single nucleotide polymorphisms. The CAGI-5 PCM1 challenge allowed us to evaluate the state of the art techniques for interpreting the effect of novel variants for a difficult target protein.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:85068522592,

title = {Assessment of patient clinical descriptions and pathogenic variants from gene panel sequences in the CAGI-5 intellectual disability challenge},

author = {Marco Carraro and Alexander Miguel Monzon and Luigi Chiricosta and Francesco Reggiani and Maria Cristina Aspromonte and Mariagrazia Bellini and Kymberleigh Pagel and Yuxiang Jiang and Predrag Radivojac and Kunal Kundu and Lipika R. Pal and Yizhou Yin and Ivan Limongelli and Gaia Andreoletti and John Moult and Stephen J. Wilson and Panagiotis Katsonis and Olivier Lichtarge and Jingqi Chen and Yaqiong Wang and Zhiqiang Hu and Steven E. Brenner and Carlo Ferrari and Alessandra Murgia and Silvio C. E. Tosatto and Emanuela Leonardi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-85068522592&origin=inward},

doi = {10.1002/humu.23823},

year  = {2019},

date = {2019-01-01},

journal = {Human Mutation},

volume = {40},

number = {9},

pages = {1330-1345},

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

abstract = {© 2019 Wiley Periodicals, Inc.The Critical Assessment of Genome Interpretation-5 intellectual disability challenge asked to use computational methods to predict patient clinical phenotypes and the causal variant(s) based on an analysis of their gene panel sequence data. Sequence data for 74 genes associated with intellectual disability (ID) and/or autism spectrum disorders (ASD) from a cohort of 150 patients with a range of neurodevelopmental manifestations (i.e. ID, autism, epilepsy, microcephaly, macrocephaly, hypotonia, ataxia) have been made available for this challenge. For each patient, predictors had to report the causative variants and which of the seven phenotypes were present. Since neurodevelopmental disorders are characterized by strong comorbidity, tested individuals often present more than one pathological condition. Considering the overall clinical manifestation of each patient, the correct phenotype has been predicted by at least one group for 93 individuals (62%). ID and ASD were the best predicted among the seven phenotypic traits. Also, causative or potentially pathogenic variants were predicted correctly by at least one group. However, the prediction of the correct causative variant seems to be insufficient to predict the correct phenotype. In some cases, the correct prediction has been supported by rare or common variants in genes different from the causative one.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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: 20; 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: 45; 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: 17; 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: 1093; 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: 280; 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: 3336; 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.P.O.Box 18667NewarkNJ 07191-8667},

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: 5},

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: 16; 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: 33; 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: 21; 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: 56; 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: 36; 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: 42; 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: 18; Open Access},

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: 52; 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: 9; 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: 22; Open Access},

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: 162; 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: 10; 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: 4},

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: 1; 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: 3},

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: 16; 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.P.O.Box 18667NewarkNJ 07191-8667},

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}

}