PUBLICATIONS

@article{SCOPUS_ID:84885843727,

title = {A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy},

author = {Gregianin and Vazza and Scaramel and Boaretto and Vettori and Leonardi and Tosatto and Manara and Pegoraro and Mostacciuolo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84885843727&origin=inward},

doi = {10.1111/ene.12220},

year  = {2013},

date = {2013-01-01},

journal = {European Journal of Neurology},

volume = {20},

number = {11},

pages = {1486-1491},

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

abstract = {Background and purpose: Mutations in the SACS gene are commonly associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a complex neurodegenerative disorder characterized by progressive degeneration of the cerebellum and spinal cord tracts. The aim of this study was to identify the genetic cause of the disease in an Italian family with spastic paraplegia and peripheral neuropathy. Methods: Affected subjects were subjected to a comprehensive neurological examination including electromyography and brain magnetic resonance imaging. Genetic studies included exclusion of known disease genes, genome-wide linkage analysis using high density single nucleotide polymorphism genotyping and candidate gene sequencing. Results: Molecular analyses revealed a novel missense mutation in the SACS gene (c.11,104A>G) occurring in a homozygous state in patients and absent in 700 Italian control chromosomes. The mutation led to the amino acid substitution p.Thr3702Ala in the sacsin protein, in a possible protein-protein interaction site of UBE3A binding domain. Conclusion: This study broadens the genetic spectrum of SACS mutations and expands the clinical ARSACS phenotype suggesting that the SACS gene can be considered in patients with non-canonical ARSACS clinical presentations. © 2013 EFNS.},

note = {Cited by: 27; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84874663959,

title = {A large-scale evaluation of computational protein function prediction},

author = {Predrag Radivojac and Wyatt T. Clark and Tal Ronnen Oron and Alexandra M. Schnoes and Tobias Wittkop and Artem Sokolov and Kiley Graim and Christopher Funk and Karin Verspoor and Asa Ben-Hur and Gaurav Pandey and Jeffrey M. Yunes and Ameet S. Talwalkar and Susanna Repo and Michael L. Souza and Damiano Piovesan and Rita Casadio and Zheng Wang and Jianlin Cheng and Hai Fang and Julian Gough and Patrik Koskinen and Petri Törönen and Jussi Nokso-Koivisto and Liisa Holm and Domenico Cozzetto and Daniel W. A. Buchan and Kevin Bryson and David T. Jones and Bhakti Limaye and Harshal Inamdar and Avik Datta and Sunitha K. Manjari and Rajendra Joshi and Meghana Chitale and Daisuke Kihara and Andreas M. Lisewski and Serkan Erdin and Eric Venner and Olivier Lichtarge and Robert Rentzsch and Haixuan Yang and Alfonso E. Romero and Prajwal Bhat and Alberto Paccanaro and Tobias Hamp and Rebecca Kaßner and Stefan Seemayer and Esmeralda Vicedo and Christian Schaefer and Dominik Achten and Florian Auer and Ariane Boehm and Tatjana Braun and Maximilian Hecht and Mark Heron and Peter Hönigschmid and Thomas A. Hopf and Stefanie Kaufmann and Michael Kiening and Denis Krompass and Cedric Landerer and Yannick Mahlich and Manfred Roos and Jari Björne and Tapio Salakoski and Andrew Wong and Hagit Shatkay and Fanny Gatzmann and Ingolf Sommer and Mark N. Wass and Michael J. E. Sternberg and Nives Škunca and Fran Supek and Matko Bošnjak and Panče Panov and Sašo Džeroski and Tomislav Šmuc and Yiannis A. I. Kourmpetis and Aalt D. J. Van Dijk and Cajo J. F. Ter Braak and Yuanpeng Zhou and Qingtian Gong and Xinran Dong and Weidong Tian and Marco Falda and Paolo Fontana and Enrico Lavezzo and Barbara Di Camillo and Stefano Toppo and Liang Lan and Nemanja Djuric and Yuhong Guo and Slobodan Vucetic and Amos Bairoch and Michal Linial and Patricia C. Babbitt and Steven E. Brenner and Christine Orengo and Burkhard Rost and ...},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84874663959&origin=inward},

doi = {10.1038/nmeth.2340},

year  = {2013},

date = {2013-01-01},

journal = {Nature Methods},

volume = {10},

number = {3},

pages = {221-227},

abstract = {Automated annotation of protein function is challenging. As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally. If computational predictions are to be relied upon, it is crucial that the accuracy of these methods be high. Here we report the results from the first large-scale community-based critical assessment of protein function annotation (CAFA) experiment. Fifty-four methods representing the state of the art for protein function prediction were evaluated on a target set of 866 proteins from 11 organisms. Two findings stand out: (i) today's best protein function prediction algorithms substantially outperform widely used first-generation methods, with large gains on all types of targets; and (ii) although the top methods perform well enough to guide experiments, there is considerable need for improvement of currently available tools. © 2013 Nature America, Inc. All rights reserved.},

note = {Cited by: 808; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84885748326,

title = {Seasonal variation in genetic population structure of sábalo (Prochilodus lineatus) in the Lower Uruguay River},

author = {Eva Carolina Rueda and Pedro Carriquiriborde and Alexander Miguel Monzón and Gustavo M. Somoza and Guillermo Ortí},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84885748326&origin=inward},

doi = {10.1007/s10709-013-9739-0},

year  = {2013},

date = {2013-01-01},

journal = {Genetica},

volume = {141},

number = {7-9},

pages = {401-407},

abstract = {Prochilodus lineatus is a highly migratory fish species that sustains the most important commercial fishery of Paraná-Paraguay basin. Migratory patterns are poorly known and only few population genetic studies are available for this species in the Upper Paraná. To assess genetic population structure, we genotyped a sample of 93 individuals from the Lower Uruguay River close to Gualeguaychú city (Entre Ríos, Argentina) at three different times, July 2008 (Winter), September 2008 (Spring) and May 2009 (Fall). All individuals were genotyped for 12 microsatellite loci previously found to be informative to assess populations of P. lineatus. Our results show seasonal variation of the genetic sub-structuring at this locality that may be related to the presence of different migratory stocks throughout the year. The Fall sample includes an additional genetic cluster of individuals not detected in Winter and Spring, suggesting that this species should be considered a mixed stock fishery. © 2013 Springer Science+Business Media Dordrecht.},

note = {Cited by: 29; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84888597395,

title = {Extended and robust protein sequence annotation over conservative nonhierarchical clusters: The case study of the abc transporters},

author = {Damiano Piovesan and Giuseppe Profiti and Pier Luigi Martelli and Piero Fariselli and Rita Casadio},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84888597395&origin=inward},

doi = {10.1145/2504729},

year  = {2013},

date = {2013-01-01},

journal = {ACM Journal on Emerging Technologies in Computing Systems},

volume = {9},

number = {4},

publisher = {Association for Computing Machinery},

abstract = {Genome annotation is one of the most important issues in the genomic era. The exponential growth rate of newly sequenced genomes and proteomes urges the development of fast and reliable annotation methods, suited to exploit all the information available in curated databases of protein sequences and structures. To this aim we developed BAR+, the Bologna Annotation Resource.1 The basic notion is that sequences with high identity value to a counterpart can inherit the same function/s and structure, if available. As a case study we describe how the ATP-binding domain of the ABC transporters can be found and modeled in over 30,000 new sequences not annotated before. We also mapped into BAR+ all the ABC transporters listed in the Transporter Classification DataBase2 and found that within our environment annotation could be extended to another 256,866 sequences. ©c 2013 ACM 1550-4832/2013/11-ART27 15.00.},

note = {Cited by: 2},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84884764376,

title = {2mit, an Intronic Gene of Drosophila melanogaster timeless2, Is Involved in Behavioral Plasticity},

author = {Francesca Baggio and Andrea Bozzato and Clara Benna and Emanuela Leonardi and Ottavia Romoli and Moira Cognolato and Silvio C. E. Tosatto and Rodolfo Costa and Federica Sandrelli},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84884764376&origin=inward},

doi = {10.1371/journal.pone.0076351},

year  = {2013},

date = {2013-01-01},

journal = {PLoS ONE},

volume = {8},

number = {9},

abstract = {Background:Intronic genes represent textasciitilde 6% of the total gene complement in Drosophila melanogaster and textasciitilde 85% of them encode for proteins. We recently characterized the D. melanogaster timeless2 (tim2) gene, showing its active involvement in chromosomal stability and light synchronization of the adult circadian clock. The protein coding gene named 2mit maps on the 11th tim2 intron in the opposite transcriptional orientation.Methodology/Principal Findings:Here we report the molecular and functional characterization of 2mit. The 2mit gene is expressed throughout Drosophila development, localizing mainly in the nervous system during embryogenesis and mostly in the mushroom bodies and ellipsoid body of the central complex in the adult brain. In silico analyses revealed that 2mit encodes a putative leucine-Rich Repeat transmembrane receptor with intrinsically disordered regions, harboring several fully conserved functional interaction motifs in the cytosolic side. Using insertional mutations, tissue-specific over-expression, and down-regulation approaches, it was found that 2mit is implicated in adult short-term memory, assessed by a courtship conditioning assay. In D. melanogaster, tim2 and 2mit do not seem to be functionally related. Bioinformatic analyses identified 2MIT orthologs in 21 Drosophilidae, 4 Lepidoptera and in Apis mellifera. In addition, the tim2-2mit host-nested gene organization was shown to be present in A. mellifera and maintained among Drosophila species. Within the Drosophilidae 2mit-hosting tim2 intron, in silico approaches detected a neuronal specific transcriptional binding site which might have contributed to preserve the specific host-nested gene association across Drosophila species. Conclusions/Significance:Taken together, these results indicate that 2mit, a gene mainly expressed in the nervous system, has a role in the behavioral plasticity of the adult Drosophila. The presence of a putative 2mit regulatory enhancer within the 2mit-hosting tim2 intron could be considered an evolutionary constraint potentially involved in maintaining the tim2-2mit host-nested chromosomal architecture during the evolution of Drosophila species. © 2013 Baggio et al.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84897366399,

title = {CoDNaS: A database of conformational diversity in the native state of proteins},

author = {Alexander Miguel Monzon and Ezequiel Juritz and María Silvina Fornasari and Gustavo Parisi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84897366399&origin=inward},

doi = {10.1093/bioinformatics/btt405},

year  = {2013},

date = {2013-01-01},

journal = {Bioinformatics},

volume = {29},

number = {19},

pages = {2512-2514},

publisher = {Oxford University Press},

abstract = {Motivation: Conformational diversity is a key concept in the understanding of different issues related with protein function such as the study of catalytic processes in enzymes, protein-protein recognition, protein evolution and the origins of new biological functions. Here, we present a database of proteins with different degrees of conformational diversity. Conformational Diversity of Native State (CoDNaS) is a redundant collection of three-dimensional structures for the same protein derived from protein data bank. Structures for the same protein obtained under different crystallographic conditions have been associated with snapshots of protein dynamism and consequently could characterize protein conformers. CoDNaS allows the user to explore global and local structural differences among conformers as a function of different parameters such as presence of ligand, post-translational modifications, changes in oligomeric states and differences in pH and temperature. Additionally, CoDNaS contains information about protein taxonomy and function, disorder level and structural classification offering useful information to explore the underlying mechanism of conformational diversity and its close relationship with protein function. Currently, CoDNaS has 122 122 structures integrating 12 684 entries, with an average of 9.63 conformers per protein. © The Author 2013.},

note = {Cited by: 29; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84887176187,

title = {Analysis and consensus of currently available intrinsic protein disorder annotation sources in the MobiDB database},

author = {Tomás Di Domenico and Ian Walsh and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84887176187&origin=inward},

doi = {10.1186/1471-2105-14-S7-S3},

year  = {2013},

date = {2013-01-01},

journal = {BMC Bioinformatics},

volume = {14},

number = {SUPPL7},

abstract = {Background: Intrinsic protein disorder is becoming an increasingly important topic in protein science. During the last few years, intrinsically disordered proteins (IDPs) have been shown to play a role in many important biological processes, e.g. protein signalling and regulation. This has sparked a need to better understand and characterize different types of IDPs, their functions and roles. Our recently published database, MobiDB, provides a centralized resource for accessing and analysing intrinsic protein disorder annotations.Results: Here, we present a thorough description and analysis of the data made available by MobiDB, providing descriptive statistics on the various available annotation sources. Version 1.2.1 of the database contains annotations for ca. 4,500,000 UniProt sequences, covering all eukaryotic proteomes. In addition, we describe a novel consensus annotation calculation and its related weighting scheme. The comparison between disorder information sources highlights how the MobiDB consensus captures the main features of intrinsic disorder and correlates well with manually curated datasets. Finally, we demonstrate the annotation of 13 eukaryotic model organisms through MobiDB's datasets, and of an example protein through the interactive user interface.Conclusions: MobiDB is a central resource for intrinsic disorder research, containing both experimental data and predictions. In the future it will be expanded to include additional information for all known proteins. © 2013 Di Domenico et al.; licensee BioMed Central Ltd.},

note = {Cited by: 27; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84876047815,

title = {Fly cryptochrome and the visual system},

author = {Gabriella Mazzotta and Alessandro Rossi and Emanuela Leonardi and Moyra Mason and Cristiano Bertolucci and Laura Caccin and Barbara Spolaore and Alberto J. M. Martin and Matthias Schlichting and Rudi Grebler and Charlotte Helfrich-Förster and Stefano Mammi and Rodolfo Costa and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84876047815&origin=inward},

doi = {10.1073/pnas.1212317110},

year  = {2013},

date = {2013-01-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {110},

number = {15},

pages = {6163-6168},

abstract = {Cryptochromes are flavoproteins, structurally and evolutionary related to photolyases, that are involved in the development, magnetoreception, and temporal organization of a variety of organisms. Drosophila CRYPTOCHROME (dCRY) is involved in light synchronization of the master circadian clock, and its C terminus plays an important role in modulating light sensitivity and activity of the protein. The activation of dCRY by light requires a conformational change, but it has been suggested that activation could be mediated also by specific "regulators" that bind the C terminus of the protein. This C-terminal region harbors several protein-protein interaction motifs, likely relevant for signal transduction regulation. Here, we show that some functional linear motifs are evolutionarily conserved in the C terminus of cryptochromes and that class III PDZ-binding sites are selectively maintained in animals. A coimmunoprecipitation assay followed by mass spectrometry analysis revealed that dCRY interacts with Retinal Degeneration A (RDGA) and with Neither Inactivation Nor Afterpotential C (NINAC) proteins. Both proteins belong to a multiprotein complex (the Signalplex) that includes visualsignaling molecules. Using bioinformatic and molecular approaches, dCRY was found to interact with Neither Inactivation Nor Afterpotential C through Inactivation No Afterpotential D (INAD) in a light-dependent manner and that the CRY-Inactivation No Afterpotential D interaction is mediated by specific domains of the two proteins and involves the CRY C terminus. Moreover, an impairment of the visual behavior was observed in fly mutants for dCRY, indicative of a role, direct or indirect, for this photoreceptor in fly vision.},

note = {Cited by: 69; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84883490214,

title = {In silico investigation of PHD-3 specific HIF1-α proline 567 hydroxylation: A new player in the VHL/HIF-1α interaction pathway?},

author = {Giovanni Minervini and Alessandro Masiero and Stefano Moro and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84883490214&origin=inward},

doi = {10.1016/j.febslet.2013.07.019},

year  = {2013},

date = {2013-01-01},

journal = {FEBS Letters},

volume = {587},

number = {18},

pages = {2996-3001},

abstract = {Hypoxia inducible factor 1α (HIF-1α) regulates oxygen homeostasis in the cell through a sensing mechanism involving its hydroxylation and binding to the von Hippel-Lindau (VHL) tumor suppressor. This mechanism is mediated through hydroxylation of HIF-1α proline 564, although in vitro tests have previously shown an alternative hydroxylation at proline 567 by PHD-3. Here, molecular dynamics simulations were used to investigate the structural effect of this alternative hydroxylation. A specific hydrogen bond network rearrangement and improved electrostatic energy for hydroxylated P567 are compatible with an increase in HIF-1α binding affinity. Sequence analysis also confirms P567 to be vastly conserved during evolution, indicating a possible role for this alternative, PHD-3 driven, post translational modification in pVHL-HIF-1α complex formation.© 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.},

note = {Cited by: 11; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84865101042,

title = {Bluues server: Electrostatic properties of wild-type and mutated protein structures},

author = {Ian Walsh and Giovanni Minervini and Alessandra Corazza and Gennaro Esposito and Silvio C. E. Tosatto and Federico Fogolari},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84865101042&origin=inward},

doi = {10.1093/bioinformatics/bts343},

year  = {2012},

date = {2012-01-01},

journal = {Bioinformatics},

volume = {28},

number = {16},

pages = {2189-2190},

abstract = {Motivation: Electrostatic calculations are an important tool for deciphering many functional mechanisms in proteins. Generalized Born (GB) models offer a fast and convenient computational approximation over other implicit solvent-based electrostatic models. Here we present a novel GB-based web server, using the program Bluues, to calculate numerous electrostatic features including pKa-values and surface potentials. The output is organized allowing both experts and beginners to rapidly sift the data. A novel feature of the Bluues server is that it explicitly allows to find electrostatic differences between wild-type and mutant structures. © The Author (2012). Published by Oxford University Press. All rights reserved.},

note = {Cited by: 72; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84857170967,

title = {Espritz: Accurate and fast prediction of protein disorder},

author = {Ian Walsh and Alberto J. M. Martin and Tomàs Di domenico and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84857170967&origin=inward},

doi = {10.1093/bioinformatics/btr682},

year  = {2012},

date = {2012-01-01},

journal = {Bioinformatics},

volume = {28},

number = {4},

pages = {503-509},

abstract = {Motivation: Intrinsically disordered regions are key for the function of numerous proteins, and the scant available experimental annotations suggest the existence of different disorder flavors. While efficient predictions are required to annotate entire genomes, most existing methods require sequence profiles for disorder prediction, making them cumbersome for high-throughput applications.Results: In this work, we present an ensemble of protein disorder predictors called ESpritz. These are based on bidirectional recursive neural networks and trained on three different flavors of disorder, including a novel NMR flexibility predictor. ESpritz can produce fast and accurate sequence-only predictions, annotating entire genomes in the order of hours on a single processor core. Alternatively, a slower but slightly more accurate ESpritz variant using sequence profiles can be used for applications requiring maximum performance. Two levels of prediction confidence allow either to maximize reasonable disorder detection or to limit expected false positives to 5%. ESpritz performs consistently well on the recent CASP9 data, reaching a S w measure of 54.82 and area under the receiver operator curve of 0.856. The fast predictor is four orders of magnitude faster and remains better than most publicly available CASP9 methods, making it ideal for genomic scale predictions. Conclusions: ESpritz predicts three flavors of disorder at two distinct false positive rates, either with a fast or slower and slightly more accurate approach. Given its state-of-the-art performance, it can be especially useful for high-throughput applications. © The Author 2011. Published by Oxford University Press. All rights reserved.},

note = {Cited by: 467; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84869206683,

title = {Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy},

author = {Luca Bello and Paola Melacini and Raffaele Pezzani and Adele D'Amico and Luisa Piva and Emanuela Leonardi and Annalaura Torella and Gianni Soraru and Arianna Palmieri and Gessica Smaniotto and Bruno F. Gavassini and Andrea Vianello and Vincenzo Nigro and Enrico Bertini and Corrado Angelini and Silvio C. E. Tosatto and Elena Pegoraro},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84869206683&origin=inward},

doi = {10.1038/ejhg.2012.71},

year  = {2012},

date = {2012-01-01},

journal = {European Journal of Human Genetics},

volume = {20},

number = {12},

pages = {1234-1239},

abstract = {Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent α-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function. © 2012 Macmillan Publishers Limited All rights reserved.},

note = {Cited by: 28; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84858145212,

title = {Studying interactions by molecular dynamics simulations at high concentration},

author = {Federico Fogolari and Alessandra Corazza and Stefano Toppo and Silvio C. E. Tosatto and Paolo Viglino and Fulvio Ursini and Gennaro Esposito},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84858145212&origin=inward},

doi = {10.1155/2012/303190},

year  = {2012},

date = {2012-01-01},

journal = {Journal of Biomedicine and Biotechnology},

volume = {2012},

abstract = {Molecular dynamics simulations have been used to study molecular encounters and recognition. In recent works, simulations using high concentration of interacting molecules have been performed. In this paper, we consider the practical problems for setting up the simulation and to analyse the results of the simulation. The simulation of beta 2-microglobulin association and the simulation of the binding of hydrogen peroxide by glutathione peroxidase are provided as examples. Copyright © 2012 Federico Fogolari et al.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84865129593,

title = {MobiDB: A comprehensive database of intrinsic protein disorder annotations},

author = {Tomás Di domenico and Ian Walsh and Alberto J. M. Martin and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84865129593&origin=inward},

doi = {10.1093/bioinformatics/bts327},

year  = {2012},

date = {2012-01-01},

journal = {Bioinformatics},

volume = {28},

number = {15},

pages = {2080-2081},

abstract = {Motivation: Disordered protein regions are key to the function of numerous processes within an organism and to the determination of a protein's biological role. The most common source for protein disorder annotations, DisProt, covers only a fraction of the available sequences. Alternatively, the Protein Data Bank (PDB) has been mined for missing residues in X-ray crystallographic structures. Herein, we provide a centralized source for data on different flavours of disorder in protein structures, MobiDB, building on and expanding the content provided by already existing sources. In addition to the DisProt and PDB X-ray structures, we have added experimental information from NMR structures and five different flavours of two disorder predictors (ESpritz and IUpred). These are combined into a weighted consensus disorder used to classify disordered regions into flexible and constrained disorder. Users are encouraged to submit manual annotations through a submission form. MobiDB features experimental annotations for 17 285 proteins, covering the entire PDB and predictions for the SwissProt database, with 565 200 annotated sequences. Depending on the disorder flavour, 6-20% of the residues are predicted as disordered. © The Author 2012. Published by Oxford University Press. All rights reserved.},

note = {Cited by: 135; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84866150728,

title = {Looking for putative phenoloxidases of compound ascidians: Haemocyanin-like proteins in Polyandrocarpa misakiensis and Botryllus schlosseri},

author = {Loriano Ballarin and Nicola Franchi and Filippo Schiavon and Silvio C. E. Tosatto and Ivan Mičetić and Kazuo Kawamura},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84866150728&origin=inward},

doi = {10.1016/j.dci.2012.05.008},

year  = {2012},

date = {2012-01-01},

journal = {Developmental and Comparative Immunology},

volume = {38},

number = {2},

pages = {232-242},

publisher = {Elsevier Ltd},

abstract = {Phenoloxidases (POs) and haemocyanins constitute a family of copper-containing proteins widely distributed among invertebrates. Both of them are able, under appropriate conditions, to convert polyphenols to quinones and induce cytotoxicity through the production of reactive oxygen species, a fundamental event in many immune responses. In ascidians, PO activity has been described and studied in both solitary and colonial species and the enzyme is involved in inflammatory and cytotoxic reactions against foreign cells or molecules, and in the formation of the cytotoxic foci which characterise the nonfusion reaction of botryllids. Expressed genes for two putative POs (CiPO1 and CiPO2) have been recently identified in C. intestinalis. In the present study, we determined the cDNA sequences of two haemocyanin-like proteins from two colonial ascidians: Botryllus schlosseri from the Mediterranean Sea and Polyandrocarpa misakiensis from Japan. Multiple sequence alignments evidenced the similarity between the above sequences and crustacean proPOs whereas the analysis of the three-dimensional structure reveals high similarity with arthropod haemocyanins which share common precursors with arthropod proPOs. Botryllus HLP grouped in the same cluster with Ciona POs, whereas Polyandrocarpa HLP clustered with arthropod haemocyanins; all of them share the full conservation of the six histidines at the two copper-binding sites as well as of other motifs, also found in arthropod haemocyanin subunits, involved in the regulation of enzyme activity. In situ hybridisation indicated that the genes are transcribed inside morula cells, a characteristic haemocyte type in ascidians where PO activity is located, at the beginning of their differentiation. These results represent a first attempt to identify candidate molecules responsible of the PO activity in compound ascidians. © 2012 Elsevier Ltd.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84870806739,

title = {RAPHAEL: Recognition, periodicity and insertion assignment of solenoid protein structures},

author = {Ian Walsh and Francesco G. Sirocco and Giovanni Minervini and Tomás Di Domenico and Carlo Ferrari and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84870806739&origin=inward},

doi = {10.1093/bioinformatics/bts550},

year  = {2012},

date = {2012-01-01},

journal = {Bioinformatics},

volume = {28},

number = {24},

pages = {3257-3264},

abstract = {Motivation: Repeat proteins form a distinct class of structures where folding is greatly simplified. Several classes have been defined, with solenoid repeats of periodicity between ca. 5 and 40 being the most challenging to detect. Such proteins evolve quickly and their periodicity may be rapidly hidden at sequence level. From a structural point of view, finding solenoids may be complicated by the presence of insertions or multiple domains. To the best of our knowledge, no automated methods are available to characterize solenoid repeats from structure. Results: Here we introduce RAPHAEL, a novel method for the detection of solenoids in protein structures. It reliably solves three problems of increasing difficulty: (1) recognition of solenoid domains, (2) determination of their periodicity and (3) assignment of insertions. RAPHAEL uses a geometric approach mimicking manual classification, producing several numeric parameters that are optimized for maximum performance. The resulting method is very accurate, with 89.5% of solenoid proteins and 97.2% of non-solenoid proteins correctly classified. RAPHAEL periodicities have a Spearman correlation coefficient of 0.877 against the manually established ones. A baseline algorithm for insertion detection in identified solenoids has a Q2 value of 79.8%, suggesting room for further improvement. RAPHAEL finds 1931 highly confident repeat structures not previously annotated as solenoids in the Protein Data Bank records. © 2012 The Author.},

note = {Cited by: 27; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84872285924,

title = {The human "magnesome": Detecting magnesium binding sites on human proteins},

author = {Damiano Piovesan and Giuseppe Profiti and Pier Luigi Martelli and Rita Casadio},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84872285924&origin=inward},

doi = {10.1186/1471-2105-13-S14-S10},

year  = {2012},

date = {2012-01-01},

journal = {BMC Bioinformatics},

volume = {13},

number = {SUPPL 1},

abstract = {Background: Magnesium research is increasing in molecular medicine due to the relevance of this ion in several important biological processes and associated molecular pathogeneses. It is still difficult to predict from the protein covalent structure whether a human chain is or not involved in magnesium binding. This is mainly due to little information on the structural characteristics of magnesium binding sites in proteins and protein complexes. Magnesium binding features, differently from those of other divalent cations such as calcium and zinc, are elusive. Here we address a question that is relevant in protein annotation: how many human proteins can bind Mg2+? Our analysis is performed taking advantage of the recently implemented Bologna Annotation Resource (BAR-PLUS), a non hierarchical clustering method that relies on the pair wise sequence comparison of about 14 millions proteins from over 300.000 species and their grouping into clusters where annotation can safely be inherited after statistical validation. Results: After cluster assignment of the latest version of the human proteome, the total number of human proteins for which we can assign putative Mg binding sites is 3,751. Among these proteins, 2,688 inherit annotation directly from human templates and 1,063 inherit annotation from templates of other organisms. Protein structures are highly conserved inside a given cluster. Transfer of structural properties is possible after alignment of a given sequence with the protein structures that characterise a given cluster as obtained with a Hidden Markov Model (HMM) based procedure. Interestingly a set of 370 human sequences inherit Mg2+ binding sites from templates sharing less than 30% sequence identity with the template. Conclusion: We describe and deliver the "human magnesome", a set of proteins of the human proteome that inherit putative binding of magnesium ions. With our BAR-hMG, 251 clusters including 1,341 magnesium binding protein structures corresponding to 387 sequences are sufficient to annotate some 13,689 residues in 3,751 human sequences as "magnesium binding". Protein structures act therefore as three dimensional seeds for structural and functional annotation of human sequences. The data base collects specifically all the human proteins that can be annotated according to our procedure as "magnesium binding", the corresponding structures and BAR+ clusters from where they derive the annotation (http://bar.biocomp.unibo.it/mg). © 2012 Piovesan et al.; licensee BioMed Central Ltd.},

note = {Cited by: 29; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84861209926,

title = {Do natural proteins differ from random sequences polypeptides? natural vs. random proteins classification using an evolutionary neural network},

author = {Davide Lucrezia and Debora Slanzi and Irene Poli and Fabio Polticelli and Giovanni Minervini},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84861209926&origin=inward},

doi = {10.1371/journal.pone.0036634},

year  = {2012},

date = {2012-01-01},

journal = {PLoS ONE},

volume = {7},

number = {5},

abstract = {Are extant proteins the exquisite result of natural selection or are they random sequences slightly edited by evolution? This question has puzzled biochemists for long time and several groups have addressed this issue comparing natural protein sequences to completely random ones coming to contradicting conclusions. Previous works in literature focused on the analysis of primary structure in an attempt to identify possible signature of evolutionary editing. Conversely, in this work we compare a set of 762 natural proteins with an average length of 70 amino acids and an equal number of completely random ones of comparable length on the basis of their structural features. We use an ad hoc Evolutionary Neural Network Algorithm (ENNA) in order to assess whether and to what extent natural proteins are edited from random polypeptides employing 11 different structure-related variables (i.e. net charge, volume, surface area, coil, alpha helix, beta sheet, percentage of coil, percentage of alpha helix, percentage of beta sheet, percentage of secondary structure and surface hydrophobicity). The ENNA algorithm is capable to correctly distinguish natural proteins from random ones with an accuracy of 94.36%. Furthermore, we study the structural features of 32 random polypeptides misclassified as natural ones to unveil any structural similarity to natural proteins. Results show that random proteins misclassified by the ENNA algorithm exhibit a significant fold similarity to portions or subdomains of extant proteins at atomic resolution. Altogether, our results suggest that natural proteins are significantly edited from random polypeptides and evolutionary editing can be readily detected analyzing structural features. Furthermore, we also show that the ENNA, employing simple structural descriptors, can predict whether a protein chain is natural or random. © 2012 De Lucrezia et al.},

note = {Cited by: 22; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79959956361,

title = {CSpritz: Accurate prediction of protein disorder segments with annotation for homology, secondary structure and linear motifs},

author = {Ian Walsh and Alberto J. M. Martin and Toms Di Domenico and Alessandro Vullo and Gianluca Pollastri and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79959956361&origin=inward},

doi = {10.1093/nar/gkr411},

year  = {2011},

date = {2011-01-01},

journal = {Nucleic Acids Research},

volume = {39},

number = {SUPPL. 2},

abstract = {CSpritz is a web server for the prediction of intrinsic protein disorder. It is a combination of previous Spritz with two novel orthogonal systems developed by our group (Punch and ESpritz). Punch is based on sequence and structural templates trained with support vector machines. ESpritz is an efficient single sequence method based on bidirectional recursive neural networks. Spritz was extended to filter predictions based on structural homologues. After extensive testing, predictions are combined by averaging their probabilities. The CSpritz website can elaborate single or multiple predictions for either short or long disorder. The server provides a global output page, for download and simultaneous statistics of all predictions. Links are provided to each individual protein where the amino acid sequence and disorder prediction are displayed along with statistics for the individual protein. As a novel feature, CSpritz provides information about structural homologues as well as secondary structure and short functional linear motifs in each disordered segment. Benchmarking was performed on the very recent CASP9 data, where CSpritz would have ranked consistently well with a Sw measure of 49.27 and AUC of 0.828. The server, together with help and methods pages including examples, are freely available at URL: http://protein.bio.unipd.it/cspritz/. © 2011 The Author(s).},

note = {Cited by: 78; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79959201489,

title = {The invasive Manila clam Ruditapes philippinarum (Adams and Reeve, 1850) in Northern Adriatic Sea: Population genetics assessed by an integrated molecular approach},

author = {Stefania Chiesa and Francesco Nonnis Marzano and Giovanni Minervini and Davide De Lucrezia and Gianluca Baccarani and Guido Bordignon and Irene Poli and Giampietro Ravagnan and Emanuele Argese},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79959201489&origin=inward},

doi = {10.1016/j.fishres.2011.04.013},

year  = {2011},

date = {2011-01-01},

journal = {Fisheries Research},

volume = {110},

number = {2},

pages = {259-267},

abstract = {The coastal lagoons of the Northern Adriatic Sea are among the most worldwide productive locations of Manila clam Ruditapes philippinarum. Although introduced in Italy in 1983 from the Indo-Pacific, fishing and exploitation of Manila clam improved during the years as Italy became the leading country in Europe for production of this shellfish.Despite its commercial importance, genetic structure of R. philippinarum in Northern Adriatic Sea has not been previously investigated. Here we present the first genetic study on Manila clam populations inhabiting a Mediterranean area, assessed by both mitochondrial (16S rDNA) and nuclear DNA (microsatellite loci). Our study showed that this species has a limited genetic differentiation at the mitochondrial level, but a higher rate of genetic diversity can be identified by polymorphic markers as microsatellites. In particular, out of 28 alleles, 7 private ones were recorded for the Venice Lagoon populations, 2 for those of Scardovari and one for the Po River Delta populations. These molecular markers suggest the occurrence of at least two different introduction events from different recruitment stocks, representing a powerful tool not only to assess genetic diversity of an introduced species, but also helpful information to manage aquaculture and fishery stocks, and to warrant food quality, safety and for the authentication of shellfish products, and traceabilty path. © 2011 Elsevier B.V.},

note = {Cited by: 30},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:80255127343,

title = {Design and dynamic simulation of minimal metallo-proteins},

author = {Nicolò Mazzucco and Stefano Zanconato and Davide De Lucrezia and Emanuele Argese and Irene Poli and Giovanni Minervini},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-80255127343&origin=inward},

doi = {10.1007/s00894-011-0993-8},

year  = {2011},

date = {2011-01-01},

journal = {Journal of Molecular Modeling},

volume = {17},

number = {11},

pages = {2919-2925},

abstract = {Ab initio in silico design of proteins and enzymes has emerged as a powerful tool to design application-tailored proteins and catalysts for a wide range of applications. Several enzymes exploit the unique features of metal cofactors to achieve catalytic activity otherwise unattainable through the use of only natural amino acid residues. One of the major bottlenecks in ab initio design of novel proteins relies on long-range and epistatic effects that severely limit the possibility of a rational design. Within this framework there is an ongoing effort to reduce protein length and complexity to unlock the full potential of in silico protein design. In this work we specifically address this problem designing and investigating the dynamic features of 10 in silico designed minimal metallo-proteins. In particular, in this paper we investigate whether and to what extent it is possible to design a minimal metallo-enzyme made of only residues involved in metal binding. In this research we address these questions by investigating the ability of 10 different "mini-proteins" with a length shorter than 15 residues. Molecular dynamics studies clearly show that it is possible to design a minimal protein able to bind a metal atom with the correct geometry. It is noteworthy that designed mini-proteins cannot achieve the formation of a canonical hydrophobic core, rather the metal ion provides a "metal core" around which the entire protein is organized. This opens the possibility of designing synthetic enzymes composed of only functional residues organized around a "metal core" which acts as both structural and functional determinat. © 2011 Springer-Verlag.},

note = {Cited by: 2},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79958845071,

title = {Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population},

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

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79958845071&origin=inward},

doi = {10.1111/j.1469-1809.2011.00647.x},

year  = {2011},

date = {2011-01-01},

journal = {Annals of Human Genetics},

volume = {75},

number = {4},

pages = {483-496},

abstract = {Mutational inactivation of the VHL gene is the cause of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome predisposing to haemangioblastomas, pheochromocytomas and clear-cell renal carcinomas. The gene product (pVHL) functions as an adapter in cellular processes including cell growth and apoptosis. VHL mutation analysis was carried out in 426 unrelated subjects with phenotypes ranging from VHL syndrome, to isolated VHL-related tumours that could represent the first manifestation of the disease. A total of 111 individuals were found to carry alterations, with large deletions representing 40% of the variants. Eighteen of the 95 detected variants were novel, seemingly disease-causing mutations; their pathogenic role has been evaluated in silico for effects on protein folding and interactions. Putative regions of interaction between pVHL and proteins involved in common pathways have been identified, assessing possible implications for the presence of mutations in these regions. All new variants predicted to truncate or cause complete pVHL loss of structure were associated with phenotypes consistent with VHL type 1. Seven of the new amino acid substitutions are disease-causing mutations, one is a neutral variant, whereas the results for two remain ambiguous. Our combined molecular and in silico approach for the evaluation of putative disease-causing mutations contributes to the interpretation of the potential pathogenicity of these novel variants. © 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.},

note = {Cited by: 21},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79959918507,

title = {BAR-PLUS: The Bologna Annotation Resource Plus for functional and structural annotation of protein sequences},

author = {Damiano Piovesan and Pier Luigi Martelli and Piero Fariselli and Andrea Zauli and Ivan Rossi and Rita Casadio},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79959918507&origin=inward},

doi = {10.1093/nar/gkr292},

year  = {2011},

date = {2011-01-01},

journal = {Nucleic Acids Research},

volume = {39},

number = {SUPPL. 2},

abstract = {We introduce BAR-PLUS (BAR+), a web server for functional and structural annotation of protein sequences. BAR+ is based on a large-scale genome cross comparison and a non-hierarchical clustering procedure characterized by a metric that ensures a reliable transfer of features within clusters. In this version, the method takes advantage of a large-scale pairwise sequence comparison of 13495736 protein chains also including 988 complete proteomes. Available sequence annotation is derived from UniProtKB, GO, Pfam and PDB. When PDB templates are present within a cluster (with or without their SCOP classification), profile Hidden Markov Models (HMMs) are computed on the basis of sequence to structure alignment and are cluster-associated (Cluster-HMM). Therefrom, a library of 10858 HMMs is made available for aligning even distantly related sequences for structural modelling. The server also provides pairwise query sequence-structural target alignments computed from the correspondent Cluster-HMM. BAR+ in its present version allows three main categories of annotation: PDB [with or without SCOP (*)] and GO and/or Pfam; PDB (*) without GO and/or Pfam; GO and/or Pfam without PDB (*) and no annotation. Each category can further comprise clusters where GO and Pfam functional annotations are or are not statistically significant. BAR+ is available at http://bar.biocomp.unibo.it/bar2.0. © 2011 The Author(s).},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79954436519,

title = {Probing mammalian spermine oxidase enzyme-substrate complex through molecular modeling, site-directed mutagenesis and biochemical characterization},

author = {Paraskevi Tavladoraki and Manuela Cervelli and Fabrizio Antonangeli and Giovanni Minervini and Pasquale Stano and Rodolfo Federico and Paolo Mariottini and Fabio Polticelli},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79954436519&origin=inward},

doi = {10.1007/s00726-010-0735-8},

year  = {2011},

date = {2011-01-01},

journal = {Amino Acids},

volume = {40},

number = {4},

pages = {1115-1126},

abstract = {Spermine oxidase (SMO) and acetylpolyamine oxidase (APAO) are FAD-dependent enzymes that are involved in the highly regulated pathways of polyamine biosynthesis and degradation. Polyamine content is strictly related to cell growth, and dysfunctions in polyamine metabolism have been linked with cancer. Specific inhibitors of SMO and APAO would allow analyzing the precise role of these enzymes in polyamine metabolism and related pathologies. However, none of the available polyamine oxidase inhibitors displays the desired characteristics of selective affinity and specificity. In addition, repeated efforts to obtain structural details at the atomic level on these two enzymes have all failed. In the present study, in an effort to better understand structure-function relationships, SMO enzyme-substrate complex has been probed through a combination of molecular modeling, site-directed mutagenesis and biochemical studies. Results obtained indicate that SMO binds spermine in a similar conformation as that observed in the yeast polyamine oxidase FMS1-spermine complex and demonstrate a major role for residues His82 and Lys367 in substrate binding and catalysis. In addition, the SMO enzyme-substrate complex highlights the presence of an active site pocket with highly polar characteristics, which may explain the different substrate specificity of SMO with respect to APAO and provide the basis for the design of specific inhibitors for SMO and APAO. © 2010 Springer-Verlag.},

note = {Cited by: 35},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79955824084,

title = {Selection dynamic of Escherichia coli host in M13 combinatorial peptide phage display libraries},

author = {Stefano Zanconato and Giovanni Minervini and Irene Poli and Davide De Lucrezia},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79955824084&origin=inward},

doi = {10.1271/bbb.110099},

year  = {2011},

date = {2011-01-01},

journal = {Bioscience, Biotechnology and Biochemistry},

volume = {75},

number = {4},

pages = {812-815},

abstract = {Phage display relies on an iterative cycle of selection and amplification of random combinatorial libraries to enrich the initial population of those peptides that satisfy a priori chosen criteria. The effectiveness of any phage display protocol depends directly on library amino acid sequence diversity and the strength of the selection procedure. In this study we monitored the dynamics of the selective pressure exerted by the host organism on a random peptide library in the absence of any additional selection pressure. The results indicate that sequence censorship exerted by Escherichia coli dramatically reduces library diversity and can significantly impair phage display effectiveness.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79954525041,

title = {Familial temporal lobe epilepsy with psychic auras associated with a novel LGI1 mutation},

author = {Striano and Busolin and Santulli and Leonardi and Coppola and Vitiello and Rigon and Michelucci and Tosatto and Striano and Nobile},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79954525041&origin=inward},

doi = {10.1212/WNL.0b013e318212ab2e},

year  = {2011},

date = {2011-01-01},

journal = {Neurology},

volume = {76},

number = {13},

pages = {1173-1176},

publisher = {Lippincott Williams and Wilkins},

abstract = {Background: Autosomal dominant lateral temporal epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the LGI1 gene have been reported in up to 50% of ADLTE pedigrees. We report a family with temporal lobe epilepsy characterized by psychic symptoms associated with a novel LGI1 mutation. Methods: All participants were personally interviewed and underwent neurologic examination and video-EEG recordings. LGI1 exons were sequenced by standard methods. Mutant cDNA was transfected into human embryonic kidney 293 cells; both cell lysates and media were analyzed by Western blot. In silico modeling of the Lgi1 protein EPTP domain was carried out using the structure of WD repeat protein and manually refined. Results: Three affected family members were ascertained, 2 of whom had temporal epilepsy with psychic symptoms (déjà vu, fear) but no auditory or aphasic phenomena, while the third had complex partial seizures without any aura. In all patients, we found a novel LGI1 mutation, Arg407Cys, which did not hamper protein secretion in vitro. Mapping of the mutation on a 3-dimensional protein model showed that this mutation does not induce large structural rearrangements but could destabilize interactions of Lgi1 with target proteins. Conclusions: The Arg407Cys is the first mutation with no effect on Lgi1 protein secretion. The uncommon, isolated psychic symptoms associated with it suggests that ADLTE encompasses a wider range of auras of temporal origin than hitherto reported. © 2011 by AAN Enterprises, Inc. All rights reseved.},

note = {Cited by: 44},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79960149420,

title = {RING: networking interacting residues, evolutionary information and energetics in protein structures},

author = {Alberto J. M. Martin and Michele Vidotto and Filippo Boscariol and Tomàs Di Domenico and Ian Walsh and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79960149420&origin=inward},

doi = {10.1093/bioinformatics/btr191},

year  = {2011},

date = {2011-01-01},

journal = {Bioinformatics},

volume = {27},

number = {14},

pages = {2003-2005},

abstract = {Motivation: Residue interaction networks (RINs) have been used in the literature to describe the protein 3D structure as a graph where nodes represent residues and edges physico-chemical interactions, e.g. hydrogen bonds or van-der-Waals contacts. Topological network parameters can be calculated over RINs and have been correlated with various aspects of protein structure and function. Here we present a novel web server, RING, to construct physico-chemically valid RINs interactively from PDB files for subsequent visualization in the Cytoscape platform. The additional structure-based parameters secondary structure, solvent accessibility and experimental uncertainty can be combined with information regarding residue conservation, mutual information and residue-based energy scoring functions. Different visualization styles are provided to facilitate visualization and standard plugins can be used to calculate topological parameters in Cytoscape. A sample use case analyzing the active site of glutathione peroxidase is presented. © The Author 2011. Published by Oxford University Press. All rights reserved.},

note = {Cited by: 123; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79953202854,

title = {A computational model of the LGI1 protein suggests a common binding site for ADAM proteins},

author = {Emanuela Leonardi and Simonetta Andreazza and Stefano Vanin and Giorgia Busolin and Carlo Nobile and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79953202854&origin=inward},

doi = {10.1371/journal.pone.0018142},

year  = {2011},

date = {2011-01-01},

journal = {PLoS ONE},

volume = {6},

number = {3},

abstract = {Mutations of human leucine-rich glioma inactivated (LGI1) gene encoding the epitempin protein cause autosomal dominant temporal lateral epilepsy (ADTLE), a rare familial partial epileptic syndrome. The LGI1 gene seems to have a role on the transmission of neuronal messages but the exact molecular mechanism remains unclear. In contrast to other genes involved in epileptic disorders, epitempin shows no homology with known ion channel genes but contains two domains, composed of repeated structural units, known to mediate protein-protein interactions. A three dimensional in silico model of the two epitempin domains was built to predict the structure-function relationship and propose a functional model integrating previous experimental findings. Conserved and electrostatic charged regions of the model surface suggest a possible arrangement between the two domains and identifies a possible ADAM protein binding site in the β-propeller domain and another protein binding site in the leucine-rich repeat domain. The functional model indicates that epitempin could mediate the interaction between proteins localized to different synaptic sides in a static way, by forming a dimer, or in a dynamic way, by binding proteins at different times. The model was also used to predict effects of known disease-causing missense mutations. Most of the variants are predicted to alter protein folding while several other map to functional surface regions. In agreement with experimental evidence, this suggests that non-secreted LGI1 mutants could be retained within the cell by quality control mechanisms or by altering interactions required for the secretion process. © 2011 Leonardi et al.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79955536128,

title = {Immune roles of a rhamnose-binding lectin in the colonial ascidian Botryllus schlosseri},

author = {Nicola Franchi and Filippo Schiavon and Matteo Carletto and Fabio Gasparini and Giulio Bertoloni and Silvio C. E. Tosatto and Loriano Ballarin},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79955536128&origin=inward},

doi = {10.1016/j.imbio.2010.10.011},

year  = {2011},

date = {2011-01-01},

journal = {Immunobiology},

volume = {216},

number = {6},

pages = {725-736},

abstract = {The present paper describes the immune role played by a recently identified (Gasparini et al. 2008) member of the rhamnose-binding lectin (RBL) family from the colonial ascidian Botryllus schlosseri.B. schlosseri RBL (BsRBL) can activate phagocytes through: (i) induction of their directional movement towards the source of the molecule; (ii) modification of cytoskeleton, required for shape changes; (iii) stimulation of the respiratory burst, and consequent production of reactive oxygen species (ROS) with microbicidal activity, including superoxide anions and peroxides; and (iv) increase in the ability to phagocytose foreign particles. RBL also induces the synthesis and release, by cytotoxic morula cells (MCs), of cytokines recognised by anti-IL1α and anti-TNFα antibodies. At high concentrations, BsRBL induces degranulation of MCs and the consequent release of the cytotoxic enzyme phenoloxidase into the medium. Results are consistent with the existence of cross-talk between B. schlosseri immunocytes (phagocytes and MCs). In addition, a three-dimensional model for BsRBL is presented. © 2010 Elsevier GmbH.},

note = {Cited by: 41; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:77950937930,

title = {A novel WT1 gene mutation in a three-generation family with progressive isolated focal segmental glomerulosclerosis},

author = {Elisa Benetti and Gianluca Caridi and Cristina Malaventura and Monica Dagnino and Emanuela Leonardi and Lina Artifoni and Gian Marco Ghiggeri and Silvio C. E. Tosatto and Luisa Murer},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-77950937930&origin=inward},

doi = {10.2215/CJN.05670809},

year  = {2010},

date = {2010-01-01},

journal = {Clinical Journal of the American Society of Nephrology},

volume = {5},

number = {4},

pages = {698-702},

abstract = {Background and objectives: Wilms tumor-suppressor gene-1 (WT1) plays a key role in kidney development and function. WT1 mutations usually occur in exons 8 and 9 and are associated with Denys-Drash, or in intron 9 and are associated with Frasier syndrome. However, overlapping clinical and molecular features have been reported. Few familial cases have been described, with intrafamilial variability. Sporadic cases of WT1 mutations in isolated diffuse mesangial sclerosis or focal segmental glomerulosclerosis have also been reported. Design, setting, participants, & measurements: Molecular analysis of WT1 exons 8 and 9 was carried out in five members on three generations of a family with late-onset isolated proteinuria. The effect of the detected amino acid substitution on WT1 protein's structure was studied by bioinformatics tools. Results: Three family members reached end-stage renal disease in full adulthood. None had genital abnormalities or Wilms tumor. Histologic analysis in two subjects revealed focal segmental glomerulosclerosis. The novel sequence variant c. 1208G > A in WT1 exon 9 was identified in all of the affected members of the family. Conclusions: The lack of Wilms tumor or other related phenotypes suggests the expansion of WT1 gene analysis in patients with focal segmental glomerulosclerosis, regardless of age or presence of typical Denys-Drash or Frasier syndrome clinical features. Structural analysis of the mutated protein revealed that the mutation hampers zinc finger-DNA interactions, impairing target gene transcription. This finding opens up new issues about WT1 function in the maintenance of the complex gene network that regulates normal podocyte function. copyright © 2010 by the American Society of Nephrology.},

note = {Cited by: 35},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:77954780222,

title = {Spectrum and frequency of SLC26A4 mutations among czech patients with early hearing loss with and without enlarged vestibular aqueduct (EVA)},

author = {Radka Pourová and Petr Janoušek and Michal Jurovčík and Marcela Dvořáková and Marcela Malíková and Dagmar Rašková and Olga Bendová and Emanuela Leonardi and Alessandra Murgia and Zdenek Kabelka and Jaromír Astl and Pavel Seeman},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-77954780222&origin=inward},

doi = {10.1111/j.1469-1809.2010.00581.x},

year  = {2010},

date = {2010-01-01},

journal = {Annals of Human Genetics},

volume = {74},

number = {4},

pages = {299-307},

abstract = {Summary: Mutations in SLC26A4 cause Pendred syndrome (PS) - hearing loss with goitre - or DFNB4 - non-syndromic hearing loss (NSHL) with inner ear abnormalities such as Enlarged Vestibular Aqueduct (EVA) or Mondini Dysplasia (MD). We tested 303 unrelated Czech patients with early hearing loss (298 with NSHL and 5 with PS), all GJB2-negative, for SLC26A4 mutations and evaluated their clinical and radiological phenotype. Among 115 available HRCT/MRI scans we detected three MD (2.6%), three Mondini-like affections (2.6%), 16 EVA (13 bilateral - 19.2% and 15.6% respectively) and 61 EVA/MD-negative scans (73.4%). We found mutation(s) in 26 patients (8.6%) and biallelic mutations in eight patients (2.7%) out of 303 tested. In 18 of 26 (69%) patients, no second mutation could be detected even using MLPA. The spectrum of SLC26A4 mutations in Czech patients is broad without any prevalent mutation. We detected 21 different mutations (four novel). The most frequent mutations were p.Val138Phe and p.Leu445Trp (18% and 8.9% of pathogenic alleles respectively). Among 13 patients with bilateral EVA, six patients (50%) carry biallelic mutations. In EVA -negative patients no biallelic mutations were found but 4.9% had monoallelic mutations. SLC26A4 mutations are present mostly in patients with EVA/MD and/or progressive HL and those with affected siblings. © 2010 The Authors Journal compilation.},

note = {Cited by: 37},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:77953504734,

title = {FRASS: The web-server for RNA structural comparison},

author = {Svetlana Kirillova and Silvio C. E. Tosatto and Oliviero Carugo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-77953504734&origin=inward},

doi = {10.1186/1471-2105-11-327},

year  = {2010},

date = {2010-01-01},

journal = {BMC Bioinformatics},

volume = {11},

abstract = {Background: The impressive increase of novel RNA structures, during the past few years, demands automated methods for structure comparison. While many algorithms handle only small motifs, few techniques, developed in recent years, (ARTS, DIAL, SARA, SARSA, and LaJolla) are available for the structural comparison of large and intact RNA molecules.Results: The FRASS web-server represents a RNA chain with its Gauss integrals and allows one to compare structures of RNA chains and to find similar entries in a database derived from the Protein Data Bank. We observed that FRASS scores correlate well with the ARTS and LaJolla similarity scores. Moreover, the-web server can also reproduce satisfactorily the DARTS classification of RNA 3D structures and the classification of the SCOR functions that was obtained by the SARA method.Conclusions: The FRASS web-server can be easily used to detect relationships among RNA molecules and to scan efficiently the rapidly enlarging structural databases. © 2010 Kirillova et al; licensee BioMed Central Ltd.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:77953261311,

title = {A cry from the krill},

author = {Gabriella M. Mazzotta and Cristiano De Pitt and Clara Benna and Silvio C. E. Tosatto and Gerolamo Lanfranchi and Cristiano Bertolucci and Rodolfo Costa},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-77953261311&origin=inward},

doi = {10.3109/07420521003697494},

year  = {2010},

date = {2010-01-01},

journal = {Chronobiology International},

volume = {27},

number = {3},

pages = {425-445},

abstract = {Antarctic krill (Euphausia superba) inhabit a region with strong seasonality in several parameters, such as photoperiod, light intensity, extent of sea ice, and food availability. In particular, seasonal changes in environmental light regimes have been shown to strongly influence krill metabolism, representing control signals for seasonal regulation of physiology of this key Southern Ocean species. Here, we report the identification of a cryptochrome gene, a cardinal component of the clockwork machinery in several organisms. EsCRY appears to be an ortholog of mammalian-like CRYs and clusters with the insect CRY2 subfamily. EsCRY has the canonical bipartite CRY structure, with a conserved N-terminal domain and a highly divergent C-terminus, that bears several binding motifs, some of them shared with insect CRY2 and others peculiar for EsCRY. We have evaluated the temporal expression of Escry both at mRNA and protein levels in individuals harvested from the Ross Sea at different times throughout the 24h cycle during the Antarctic summer. We observed a daily fluctuation in abundance for Escry mRNA in the head, with high levels around 06:00h, which is not mirrored by a cycle in the corresponding protein. Our findings represent a first step toward establishing the presence of an endogenous circadian time-keeping mechanism that might allow this organism to synchronize its physiology and behavior to the Antarctic light regimes. © Informa UK Ltd.},

note = {Cited by: 26},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:77957277448,

title = {Deletions and mutations in the acidic lipid-binding region of the plasma membrane Ca2+ pump: A study on different splicing variants of isoform 2},

author = {Marisa Brini and Francesca Di Leva and Claudia K. Ortega and Teuta Domi and Denis Ottolini and Emanuela Leonardi and Silvio C. E. Tosatto and Ernesto Carafoli},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-77957277448&origin=inward},

doi = {10.1074/jbc.M110.140475},

year  = {2010},

date = {2010-01-01},

journal = {Journal of Biological Chemistry},

volume = {285},

number = {40},

pages = {30779-30791},

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

abstract = {Acidic phospholipids increase the affinity of the plasma membrane Ca 2+-ATPase pump for Ca2+. They interact with the C-terminal region of the pump and with a domain in the loop connecting transmembrane domains 2 and 3 (AL region) next to site A of alternative splicing. The contribution of the two phospholipid-binding sites and the possible interference of splicing inserts at site A with the regulation of the ATPase activity of isoform 2 of the pump by phospholipids have been analyzed. The activity of the full-length z/b variant (no insert at site A), the w/b (with insert at site A), and the w/a variant, containing both the 45-amino acid A-site insert and a C-site insert that truncates the pump in the calmodulin binding domain, has been analyzed in microsomal membranes of overexpressing CHO cells. The A-site insertion did not modify the phospholipid sensitivity of the pump, but the doubly inserted w/a variant became insensitive to acidic phospholipids, even if containing the intact AL phospholipid binding domain. Pump mutants in which 12 amino acids had been deleted, or single lysine mutations introduced, in the AL region were studied by monitoring agonist-induced Ca2+ transients in overexpressing CHO cells. The 12-residue deletion completely abolished the ATPase activity of the w/a variant but only reduced that of the z/b variant, which was also affected by the single lysine substitutions in the same domain. A structural interpretation of the interplay of the pump with phospholipids, and of the mechanism of their activation, is proposed on the basis of molecular modeling studies. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.},

note = {Cited by: 22; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:78149244240,

title = {MOBI: A web server to define and visualize structural mobility in NMR protein ensembles},

author = {Alberto J. M. Martin and Ian Walsh and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-78149244240&origin=inward},

doi = {10.1093/bioinformatics/btq537},

year  = {2010},

date = {2010-01-01},

journal = {Bioinformatics},

volume = {26},

number = {22},

pages = {2916-2917},

abstract = {Motivation: MOBI is a web server for the identification of structurally mobile regions in NMR protein ensembles. It provides a binary mobility definition that is analogous to the commonly used definition of intrinsic disorder in X-ray crystallographic structures. At least three different use cases can be envisaged: (i) visualization of NMR mobility for structural analysis; (ii) definition of regions for reliable comparative modelling in protein structure prediction and (iii) definition of mobility in analogy to intrinsic disorder. MOBI uses structural superposition and local conformational differences to derive a robust binary mobility definition that is in excellent agreement with the manually curated definition used in the CASP8 experiment for intrinsic disorder in NMR structure. The output includes mobility-coloured PDB files, mobility plots and a FASTA formatted sequence file summarizing the mobility results. © The Author 2010. Published by Oxford University Press. All rights reserved.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:74249088516,

title = {Global and local model quality estimation at CASP8 using the scoring functions QMEAN and QMEANclust},

author = {Pascal Benkert and Silvio C. E. Tosatto and Torsten Schwede},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-74249088516&origin=inward},

doi = {10.1002/prot.22532},

year  = {2009},

date = {2009-01-01},

journal = {Proteins: Structure, Function and Bioinformatics},

volume = {77},

number = {SUPPL. 9},

pages = {173-180},

abstract = {Identifying the best candidate model among an ensemble of alternatives is crucial in protein structure prediction. For this purpose, scoring functions have been developed which either calculate a quality estimate on the basis of a single model or derive a score from the information contained in the ensemble of models generated for a given sequence (i.e., consensus methods). At CASP7, consensus methods have performed considerably better than scoring functions operating on single models. However, consensus methods tend to fail if the best models are far from the center of the dominant structural cluster. At CASP8, we investigated whether our hybrid method QMEANclust may overcome this limitation by combining the QMEAN composite scoring function operating on single models with consensus information. We participated with four different scoring functions in the quality assessment category. The QMEANclust consensus scoring function turned out to be a successful method both for the ranking of entire models but especially for the estimation of the per-residue model quality. In this article, we briefly describe the two scoring functions QMEAN and QMEANclust and discuss their performance in the context of what went right and wrong at CASP8. Both scoring functions are publicly available at http://swissmodel. expasy.org/qmean/. © 2009 WILEY-LISS, INC.},

note = {Cited by: 53},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:66349088076,

title = {REPETITA: Detection and discrimination of the periodicity of protein solenoid repeats by discrete Fourier transform},

author = {Luca Marsella and Francesco Sirocco and Antonio Trovato and Flavio Seno and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-66349088076&origin=inward},

doi = {10.1093/bioinformatics/btp232},

year  = {2009},

date = {2009-01-01},

journal = {Bioinformatics},

volume = {25},

number = {12},

publisher = {Oxford University Press},

abstract = {Motivation: Proteins with solenoid repeats evolve more quickly than non-repetitive ones and their periodicity may be rapidly hidden at sequence level, while still evident in structure. In order to identify these repeats, we propose here a novel method based on a metric characterizing amino-acid properties (polarity, secondary structure, molecular volume, codon diversity, electric charge) using five previously derived numerical functions. Results: The five spectra of the candidate sequences coding for structural repeats, obtained by Discrete Fourier Transform (DFT), show common features allowing determination of repeat periodicity with excellent results. Moreover it is possible to introduce a phase space parameterized by two quantities related to the Fourier spectra which allow for a clear distinction between a non-homologous set of globular proteins and proteins with solenoid repeats. The DFT method is shown to be competitive with other state of the art methods in the detection of solenoid structures, while improving its performance especially in the identification of periodicities, since it is able to recognize the actual repeat length in most cases. Moreover it highlights the relevance of local structural propensities in determining solenoid repeats. © 2009 The Author(s).},

note = {Cited by: 59; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:74749091402,

title = {In silico structural study of random amino acid sequence proteins not present in nature},

author = {Katarzyna Prymula and Monika Piwowar and Marek Kochanczyk and Lukasz Flis and Maciej Malawski and Tomasz Szepieniec and Giovanni Evangelista and Giuseppe Minervini and Fabio Polticelli and Zdzisław Wiśniowski and Kinga Sałapa and Ewa Matczyńska and Irena Roterman},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-74749091402&origin=inward},

doi = {10.1002/cbdv.200800338},

year  = {2009},

date = {2009-01-01},

journal = {Chemistry and Biodiversity},

volume = {6},

number = {12},

pages = {2311-2336},

abstract = {The three-dimensional structures of a set of 'never born proteins' (NBP, random amino acid sequence proteins with no significant homology with known proteins) were predicted using two methods: Rosetta and the one based on the 'fuzzy-oil-drop' (FOD) model. More than 3000 different random amino acid sequences have been generated, filtered against the non redundant protein sequence data base, to remove sequences with significant homology with known proteins, and subjected to three-dimensional structure prediction. Comparison between Rosetta and FOD predictions allowed to select the ten top (highest structural similarity) and the ten bottom (the lowest structural similarity) structures from the ranking list organized according to the RMS-D value. The selected structures were taken for detailed analysis to define the scale of structural accordance and discrepancy between the two methods. The structural similarity measurements revealed discrepancies between structures generated on the basis of the two methods. Their potential biological function appeared to be quite different as well. The ten bottom structures appeared to be 'unfoldable' for the FOD model. Some aspects of the general characteristics of the NBPs are also discussed. The calculations were performed on the EUChinaGRID grid platform to test the performance of this infrastructure for massive protein structure predictions. © 2009 Verlag Helvetica Chimica Acta AG.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:57449092576,

title = {Gamma-glutamyl transferase in the cell wall participates in extracellular glutathione salvage from the root apoplast},

author = {Ferretti and Destro and Tosatto and La Rocca and Rascio and Masi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-57449092576&origin=inward},

doi = {10.1111/j.1469-8137.2008.02653.x},

year  = {2009},

date = {2009-01-01},

journal = {New Phytologist},

volume = {181},

number = {1},

pages = {115-126},

abstract = {• The molecular properties and subcellular location of bound gamma-glutamyl transferase (GGT) were studied, and an experimental setup devised to assess its functions in barley roots. • Enzyme histochemistry was used to detect GGT activity at tissue level; immunocytochemistry to localize the protein at subcellular level; and modelling studies to investigate its surface charge properties. GGT activity in vivo was measured for the first time. Functions were explored by applying chemical treatments with inhibitors and the thiol-oxidizing drug diamide, performing time-course chromatographic and spectrophotometric analyses on low-molecular-weight thiols. • Gamma-glutamyl transferase activity was found to be high in the root apical region and the protein was anchored to root cell wall components, probably by basic amino acid residues. The results show that GGT is essential to the recovery of apoplastic glutathione provided exogenously or extruded by oxidative treatment. • It is demonstrated that GGT activity helps to salvage extracellular glutathione and may contribute to redox control of the extracellular environment, thus providing evidence of a functional role for gamma-glutamyl cycle in roots. © The Authors (2008).},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:63749094521,

title = {LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy},

author = {Carlo Nobile and Roberto Michelucci and Simonetta Andreazza and Elena Pasini and Silvio C. E. Tosatto and Pasquale Striano},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-63749094521&origin=inward},

doi = {10.1002/humu.20925},

year  = {2009},

date = {2009-01-01},

journal = {Human Mutation},

volume = {30},

number = {4},

pages = {530-536},

abstract = {Autosomal dominant lateral temporal epilepsy(ADLTE) or autosomal dominant partial epilepsy with auditory features(ADPEAF) is an inherited epileptic syndrome with onset in childhood/adolescence and benign evolution. The hallmark of the syndrome consists of typical auditory auras or ictal aphasia in most affected family members. ADTLE/ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1(LGI1) gene. In addition, de novo LGI1 mutations are found in about 2% of sporadic cases with idiopathic partial epilepsy with auditory features, who are clinically similar to the majority of patients with ADLTE/ADPEAF but have no family history. Twenty-five LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N-terminal leucine rich repeat(LRR) and C-terminal EPTP(beta propeller) protein domains. We show a tridimensional model of the LRR protein region that allows missense mutations of this region to be divided into two distinct groups: structural and functional mutations. Frameshift, nonsense and splice site point mutations have also been reported that result in protein truncation or internal deletion. The various types of mutations are associated with a rather homogeneous phenotype, and no obvious genotype- phenotype correlation can be identified. Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. The function of LGI1 is unclear. Several molecular mechanisms possibly leading to lateral temporal epilepsy are illustrated and briefly discussed. © 2009 Wiley-Liss,Inc.},

note = {Cited by: 136},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:67650465659,

title = {QMEANclust: Estimation of protein model quality by combining a composite scoring function with structural density information},

author = {Pascal Benkert and Torsten Schwede and Silvio C E Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-67650465659&origin=inward},

doi = {10.1186/1472-6807-9-35},

year  = {2009},

date = {2009-01-01},

journal = {BMC Structural Biology},

volume = {9},

publisher = {BioMed Central Ltd.},

abstract = {Background. The selection of the most accurate protein model from a set of alternatives is a crucial step in protein structure prediction both in template-based and ab initio approaches. Scoring functions have been developed which can either return a quality estimate for a single model or derive a score from the information contained in the ensemble of models for a given sequence. Local structural features occurring more frequently in the ensemble have a greater probability of being correct. Within the context of the CASP experiment, these so called consensus methods have been shown to perform considerably better in selecting good candidate models, but tend to fail if the best models are far from the dominant structural cluster. In this paper we show that model selection can be improved if both approaches are combined by pre-filtering the models used during the calculation of the structural consensus. Results. Our recently published QMEAN composite scoring function has been improved by including an all-atom interaction potential term. The preliminary model ranking based on the new QMEAN score is used to select a subset of reliable models against which the structural consensus score is calculated. This scoring function called QMEANclust achieves a correlation coefficient of predicted quality score and GDT-TS of 0.9 averaged over the 98 CASP7 targets and perform significantly better in selecting good models from the ensemble of server models than any other groups participating in the quality estimation category of CASP7. Both scoring functions are also benchmarked on the MOULDER test set consisting of 20 target proteins each with 300 alternatives models generated by MODELLER. QMEAN outperforms all other tested scoring functions operating on individual models, while the consensus method QMEANclust only works properly on decoy sets containing a certain fraction of near-native conformations. We also present a local version of QMEAN for the per-residue estimation of model quality (QMEANlocal) and compare it to a new local consensus-based approach. Conclusion. Improved model selection is obtained by using a composite scoring function operating on single models in order to enrich higher quality models which are subsequently used to calculate the structural consensus. The performance of consensus-based methods such as QMEANclust highly depends on the composition and quality of the model ensemble to be analysed. Therefore, performance estimates for consensus methods based on large meta-datasets (e.g. CASP) might overrate their applicability in more realistic modelling situations with smaller sets of models based on individual methods. © 2009 Benkert et al; licensee BioMed Central Ltd.},

note = {Cited by: 139; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:59649101806,

title = {The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane},

author = {Lucia Muraro and Silvio Tosatto and Lisa Motterlini and Ornella Rossetto and Cesare Montecucco},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-59649101806&origin=inward},

doi = {10.1016/j.bbrc.2009.01.037},

year  = {2009},

date = {2009-01-01},

journal = {Biochemical and Biophysical Research Communications},

volume = {380},

number = {1},

pages = {76-80},

abstract = {Botulinum neurotoxin type A (BoNT/A) is largely employed in human therapy because of its specific inhibition of peripheral cholinergic nerve terminals. BoNT/A binds to them rapidly and with high specificity via its receptor binding domain termed HC. Recent evidence indicate that BoNT/A interacts specifically with polysialogangliosides and with a luminal loop of the synaptic vesicle protein SV2 via the C-terminal half of HC. Here we show that the N-terminal half of HC binds to sphingomyelin-enriched membrane microdomains and that it has a defined interaction with phosphatidylinositol phosphates (PIP). We have identified a PIP binding site in this half of HC and we show how this interaction could predispose BoNT/A for membrane insertion, which is the step subsequent to binding, in the four-steps route leading BoNT/A inside nerve terminals. © 2009 Elsevier Inc. All rights reserved.},

note = {Cited by: 78},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:71749098721,

title = {Adding structural information to the von Hippel-Lindau (VHL) tumor suppressor interaction network},

author = {Leonardi and Murgia and Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-71749098721&origin=inward},

doi = {10.1016/j.febslet.2009.10.070},

year  = {2009},

date = {2009-01-01},

journal = {FEBS Letters},

volume = {583},

number = {22},

pages = {3704-3710},

abstract = {The von Hippel-Lindau (VHL) tumor suppressor gene is a protein interaction hub, controlling numerous genes implicated in tumor progression. Here we focus on structural aspects of protein interactions for a list of 35 experimentally verified protein VHL (pVHL) interactors. Using structural information and computational analysis we have located three distinct interaction interfaces (A, B, and C). Interface B is the most versatile, recognizing a refined linear motif present in 17 otherwise non-related proteins. It has been possible to distinguish compatible and exclusive interactions by relating pVHL function to interaction interfaces and subcellular localization. A novel hypothesis is presented regarding the possible function of the N-terminus as an inhibitor of pVHL function. © 2009 Federation of European Biochemical Societies.},

note = {Cited by: 22},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:67650104280,

title = {Electric dipole reorientation in the interaction of botulinum neurotoxins with neuronal membranes},

author = {Federico Fogolari and Silvio C. E. Tosatto and Lucia Muraro and Cesare Montecucco},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-67650104280&origin=inward},

doi = {10.1016/j.febslet.2009.06.046},

year  = {2009},

date = {2009-01-01},

journal = {FEBS Letters},

volume = {583},

number = {14},

pages = {2321-2325},

abstract = {Botulinum neurotoxins are highly potent toxins capable of rapid and specific interaction with the presynaptic membrane. We have hypothesised that: (1) these neurotoxins possess an electric dipole with the positive pole on receptor binding domain Hc-C and that (2) on approaching the negatively charged presynaptic membrane, they reorient themselves and hit the membrane surface with Hc-C; this electrostatic effect would contribute efficient binding. Electrostatic calculations confirm these hypotheses and strongly indicate that electrostatics effects can play an important role in the unique presynaptic membrane binding properties of these neurotoxins and generally on the interaction of other plasma membrane protein ligands. © 2009.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:55749104577,

title = {TESE: Generating specific protein structure test set ensembles},

author = {Francesco Sirocco and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-55749104577&origin=inward},

doi = {10.1093/bioinformatics/btn488},

year  = {2008},

date = {2008-01-01},

journal = {Bioinformatics},

volume = {24},

number = {22},

pages = {2632-2633},

abstract = {Summary: TESE is a web server for the generation of test sets of protein sequences and structures fulfilling a number of different criteria. At least three different use cases can be envisaged: (i) benchmarking of novel methods; (ii) test sets tailored for special needs and (iii) extending available datasets. The CATH structure classification is used to control structural/sequence redundancy and a variety of structural quality parameters can be used to interactively select protein subsets with specific characteristics, e.g. all X-ray structures of α-helical repeat proteins with more than 120 residues and resolution <2.0 Å. The output includes FASTA-formatted sequences, PDB files and a clickable HTML index file containing images of the selected proteins. Multiple subsets for cross-validation are also supported. © The Author 2008. Published by Oxford University Press. All rights reserved.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:40549141792,

title = {QMEAN: A comprehensive scoring function for model quality assessment},

author = {Pascal Benkert and Silvio C. E. Tosatto and Dietmar Schomburg},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-40549141792&origin=inward},

doi = {10.1002/prot.21715},

year  = {2008},

date = {2008-01-01},

journal = {Proteins: Structure, Function and Genetics},

volume = {71},

number = {1},

pages = {261-277},

abstract = {In protein structure prediction, a considerable number of alternative models are usually produced from which subsequently the final model has to be selected. Thus, a scoring function for the identification of the best model within an ensemble of alternative models is a key component of most protein structure prediction pipelines. QMEAN, which stands for Qualitative Model Energy ANalysis, is a composite scoring function describing the major geometrical aspects of protein structures. Five different structural descriptors are used. The local geometry is analyzed by a new kind of torsion angle potential over three consecutive amino acids. A secondary structure-specific distance-dependent pairwise residue-level potential is used to assess long-range interactions. A solvation potential describes the burial status of the residues. Two simple terms describing the agreement of predicted and calculated secondary structure and solvent accessibility, respectively, are also included. A variety of different implementations are investigated and several approaches to combine and optimize them are discussed. QMEAN was tested on several standard decoy sets including a molecular dynamics simulation decoy set as well as on a comprehensive data set of totally 22,420 models from server predictions for the 95 targets of CASP7. In a comparison to five well-established model quality assessment programs, QMEAN shows a statistically significant improvement over nearly all quality measures describing the ability of the scoring function to identify the native structure and to discriminate good from bad models. The three-residue torsion angle potential turned out to be very effective in recognizing the native fold. © 2007 Wiley-Liss, Inc.},

note = {Cited by: 905},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:38849180102,

title = {Comparative analysis of [FeFe] hydrogenase from Thermotogales indicates the molecular basis of resistance to oxygen inactivation},

author = {Silvio C. E. Tosatto and Stefano Toppo and Donatella Carbonera and Giorgio M. Giacometti and Paola Costantini},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-38849180102&origin=inward},

doi = {10.1016/j.ijhydene.2007.10.010},

year  = {2008},

date = {2008-01-01},

journal = {International Journal of Hydrogen Energy},

volume = {33},

number = {2},

pages = {570-578},

publisher = {Elsevier Ltd},

abstract = {Several Thermotogales, previously reported as being strict anaerobes, have demonstrated the ability to grow and produce hydrogen in the presence of moderate amounts of molecular oxygen. Thermotoga neapolitana seems to be less sensitive to O2 than other members of this order, including Thermotoga maritima, whose hydrogenase has been purified and characterized. Instead, the enzyme responsible for the hydrogen production by T. neapolitana has not yet been identified. After the recent sequencing of the T. neapolitana genome, it has been possible to search for the orthologous gene responsible for this unusal hydrogenase activity. By means of in silico analysis, we built a molecular model for both T. maritima and T. neapolitana proteins and analyzed conservation, focusing on the subtle structural differences responsible for the increased oxygen resistance in the latter and underscoring two mutations (E475S and T539L) which represent a specific adaption for more effective release of hydrogen in aerobic conditions. © 2007 International Association for Hydrogen Energy.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:43449113547,

title = {Inhibitory interaction of the 14-3-3 proteins with ubiquitous (PMCA1) and tissue-specific (PMCA3) isoforms of the plasma membrane Ca2+ pump},

author = {Cristina I. Linde and Francesca Di Leva and Teuta Domi and Silvio C. E. Tosatto and Marisa Brini and Ernesto Carafoli},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-43449113547&origin=inward},

doi = {10.1016/j.ceca.2007.09.003},

year  = {2008},

date = {2008-01-01},

journal = {Cell Calcium},

volume = {43},

number = {6},

pages = {550-561},

publisher = {Elsevier Ltd},

abstract = {A previous study has demonstrated that the ubiquitous plasma membrane Ca2+ pump PMCA4 interacted with isoform ε of the 14-3-3 protein, whereas the nervous tissue-specific PMCA2 did not. The 14-3-3 proteins are widely expressed small acidic proteins, which modulate cell signaling, intracellular trafficking, transcription and apoptosis. The investigation has been extended to the other tissue-restricted pump (PMCA3) and to the other ubiquitous pump (PMCA1). At variance with PMCA2, PMCA3 interacted with the 14-3-3ε protein in a two-hybrid system assay, which could not be used for PMCA1. The 14-3-3ε protein immunoprecipitated with both PMCA3 and PMCA1 when expressed in HeLa cells. Pull-down experiments using GST-PMCA1 and GST-PMCA3 fusion products confirmed the interaction of both pumps with the 14-3-3ε protein. The binding was phosphorylation-independent with both PMCA3 and PMCA1. The 14-3-3ζ isoform also interacted with PMCA3; however, it did not interact with PMCA1. The effect of the interaction on the activity of the two pumps, and thus on the homeostasis of Ca2+, was investigated by co-expressing the 14-3-3ε protein and PMCA3 or PMCA1 in CHO cells together with the recombinant Ca2+ indicator aequorin: the ability of cells to re-establish the basal Ca2+ concentration following a Ca2+ transient induced by an InsP3-producing agonist was substantially decreased with both pumps, indicating that the interaction with the 14-3-3 protein inhibited the activity of both PMCA3 and PMCA1. © 2007 Elsevier Ltd. All rights reserved.},

note = {Cited by: 37},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:46449138673,

title = {The catalytic site of glutathione peroxidases},

author = {Silvio C. E. Tosatto and Valentina Bosello and Federico Fogolari and Pierluigi Mauri and Antonella Roveri and Stefano Toppo and Leopold Flohé and Fulvio Ursini and Matilde Maiorino},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-46449138673&origin=inward},

doi = {10.1089/ars.2008.2055},

year  = {2008},

date = {2008-01-01},

journal = {Antioxidants and Redox Signaling},

volume = {10},

number = {9},

pages = {1515-1525},

abstract = {In GPxs, the redox-active Se or S, is at hydrogen bonding distance from Gln and Trp residues that contribute to catalysis. From sequence homology of >400 sequences and modeling of the DmGPx as a paradigm, Asn136 emerged as a fourth essential component of the active site. Mutational substitution of Asn136 by His, Ala, or Asp results in a dramatic decline of specific activity. Kinetic analysis indicates that k+1, the rate constant for the oxidation of the enzyme, decreases by two to three orders of magnitude, whereas the reductive steps characterized by k′+2 are less affected. Accordingly, MS/MS analysis shows that in Asn136 mutants, the peroxidatic Cys45 stays largely reduced also in the presence of a hydroperoxide, whereas in the wild-type enzyme, it is oxidized, forming a disulfide with the resolving Cys. Computational calculation of pKa values indicates that the residues facing the catalytic thiol, Asn136, Gln80, and, to a lesser extent Trp135, contribute to the dissociation of the thiol group, Asn136 being most relevant. These data disclose that the catalytic site of GPxs has to be redrawn as a tetrad, including Asn136, and suggest a mechanism accounting for the extraordinary catalytic efficiency of GPxs. © Mary Ann Liebert, Inc. 2008.},

note = {Cited by: 166},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:46449103532,

title = {Evolutionary and structural insights into the multifaceted glutathione peroxidase (Gpx) superfamily},

author = {Stefano Toppo and Stefano Vanin and Valentina Bosello and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-46449103532&origin=inward},

doi = {10.1089/ars.2008.2057},

year  = {2008},

date = {2008-01-01},

journal = {Antioxidants and Redox Signaling},

volume = {10},

number = {9},

pages = {1501-1513},

abstract = {Glutathione peroxidase (GPx) is a widespread protein superfamily found in many organisms throughout all kingdoms of life. Although it was initially thought to use only glutathione as reductant, recent evidence suggests that the majority of GPxs have specificity for thioredoxin. We present a thorough in silico analysis performed on 724 sequences and 12 structures aimed to clarify the evolutionary, structural, and sequence determinants of GPx specificity. Structural variability was found to be limited to only two regions, termed oligomerization loop and functional helix, which modulate both reduced substrate specificity and oligomerization state. We show that mammalian GPx-1, the canonic selenocysteine-based tetrameric glutathione peroxidase, is a recent "invention" during evolution. Contrary to common belief, cysteine-based thioredoxin-specific GPx, which we propose the TGPx, are both more common and more ancient. This raises interesting evolutionary considerations regarding oligomerization and the use of active-site selenocysteine residue. In addition, phylogenetic analysis has revealed the presence of a novel member belonging to the GPx superfamily in Mammalia and Amphibia, for which we propose the name GPx-8, following the present numeric order of the mammalian GPxs. © Mary Ann Liebert, Inc. 2008.},

note = {Cited by: 228},

keywords = {},

pubstate = {published},

tppubtype = {article}

}