PUBLICATIONS

@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: 52},

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: 58; 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: 9},

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: 48; 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: 134; Open Access},

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: 134; 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: 73},

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: 20},

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: 16; 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: 857},

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: 17},

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: 30},

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: 155},

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: 218},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:54849423259,

title = {Human haptoglobin structure and function - A molecular modelling study},

author = {Polticelli and Bocedi and Minervini and Ascenzi},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-54849423259&origin=inward},

doi = {10.1111/j.1742-4658.2008.06690.x},

year  = {2008},

date = {2008-01-01},

journal = {FEBS Journal},

volume = {275},

number = {22},

pages = {5648-5656},

abstract = {Hemoglobin is the most prominent protein in blood, transporting O 2 and facilitating reactive oxygen and nitrogen species detoxification. Hemoglobin metabolism leads to the release of extra-erythrocytic hemoglobin, with potentially severe consequences for health. Extra-erythrocytic hemoglobin is complexed to haptoglobin for clearance by tissue macrophages. The human gene for haptoglobin consists of three structural alleles: Hp1F, Hp1S and Hp2. The products of the Hp1F and Hp1S alleles differ by only one amino acid, whereas the Hp2 allele is the result of a fusion of the Hp1F and Hp1S alleles, is present only in humans and gives rise to a longer α-chain. Haptoglobin consists of a dimer of αβ-chains covalently linked by a disulphide bond between the Cys15 residue of each α-chain. However, the presence of the Hp1 and Hp2 alleles in humans gives rise to HPT1-1 dimers (covalently linked by Cys15 residues), HPT1-2 hetero-oligomers and HPT2-2 oligomers. In fact, the HPT2 variant displays two free Cys residues (Cys15 and Cys74) whose participation in intermolecular disulphide bonds gives rise to higher-order covalent multimers. Here, the complete modelling of both haptoglobin variants, together with their basic quaternary structure arrangements (i.e. HPT1 dimer and HPT2 trimer), is reported. The structural details of the models, which represent the first complete view of the molecular details of human haptoglobin variants, are discussed in relation to the known haptoglobin function(s). © 2008 The Authors.},

note = {Cited by: 72},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:46749140860,

title = {Low density lipoprotein misfolding and amyloidogenesis},

author = {Tiziana Parasassi and Marco De Spirito and Giampiero Mei and Roberto Brunelli and Giulia Greco and Laura Lenzi and Giuseppe Maulucci and Eleonora Nicolai and Massimiliano Papi and Giuseppe Arcovito and Silvio C. E. Tosatto and Fulvio Ursini},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-46749140860&origin=inward},

doi = {10.1096/fj.07-097774},

year  = {2008},

date = {2008-01-01},

journal = {FASEB Journal},

volume = {22},

number = {7},

pages = {2350-2356},

abstract = {In early atherogenesis, subendothelial retention of lipidic droplets is associated with an inflammatory response-to-injury, culminating in the formation of foam cells and plaque. Low density lipoprotein (LDL) is the main constituent of subendothelial lipidic droplets. The process is believed to occur following LDL modification. Searching for a modified LDL in plasma, electronegative LDL [LDL(-)] was identified and found to be associated with major risk biomarkers. The apoprotein in LDL(-) is misfolded, and we show here that this modification primes the aggregation of native LDL, conforming to the typical pattern of protein amyloidogenesis. After a lag phase, whose length depends on LDL(-) concentration, light scattering and atomic force microscopy reveal early exponential growth of intermediate globules, which evolve into fibrils. These globules are remarkably similar to subendothelial droplets in atheromatous lesions and different from those produced by oxidation or biochemical manipulation. During aggregation, ellipticity and tryptophan fluorescence measurements reveal a domino-style spread of apoprotein misfolding from LDL(-) to all of the LDL. Computational analysis of the apoprotein primary sequence predicts an unstable, aggregation-prone domain in the regulatory α2 region. Apoprotein misfolding well represents an LDL modification able to transform this cholesterol carrier into a trigger for a response-to-injury in the artery wall. © FASEB.},

note = {Cited by: 46},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33847095044,

title = {Linear motifs in the C-terminus of D. melanogaster cryptochrome},

author = {Matthew J. Hemsley and Gabriella M. Mazzotta and Moyra Mason and Stephane Dissel and Stefano Toppo and Mario A. Pagano and Federica Sandrelli and Flavio Meggio and Ezio Rosato and Rodolfo Costa and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33847095044&origin=inward},

doi = {10.1016/j.bbrc.2007.01.189},

year  = {2007},

date = {2007-01-01},

journal = {Biochemical and Biophysical Research Communications},

volume = {355},

number = {2},

pages = {531-537},

abstract = {The C-terminus of cryptochrome (CRY) regulates light responses in Drosophila. These include the light-dependent binding of Drosophila dCRY to the clock proteins PERIOD and TIMELESS in a yeast two-hybrid system, which we proved to be a convenient and reliable readout of the behavior of dCRY in vivo. In this study, we present a combination of in silico analysis and experimental validation in yeast, to identify novel functional motifs in the C-terminal region of dCRY. Our results suggest that linear motifs are present in this small region, which is a likely hotspot for molecular interactions. © 2007 Elsevier Inc. All rights reserved.},

note = {Cited by: 30},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:34249778085,

title = {TAP score: Torsion angle propensity normalization applied to local protein structure evaluation},

author = {Silvio C. E. Tosatto and Roberto Battistutta},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-34249778085&origin=inward},

doi = {10.1186/1471-2105-8-155},

year  = {2007},

date = {2007-01-01},

journal = {BMC Bioinformatics},

volume = {8},

abstract = {Background: Experimentally determined protein structures may contain errors and require validation. Conformational criteria based on the Ramachandran plot are mainly used to distinguish between distorted and adequately refined models. While the readily available criteria are sufficient to detect totally wrong structures, establishing the more subtle differences between plausible structures remains more challenging. Results: A new criterion, called TAP score, measuring local sequence to structure fitness based on torsion angle propensities normalized against the global minimum and maximum is introduced. It is shown to be more accurate than previous methods at estimating the validity of a protein model in terms of commonly used experimental quality parameters on two test sets representing the full PDB database and a subset of obsolete PDB structures. Highly selective TAP thresholds are derived to recognize over 90% of the top experimental structures in the absence of experimental information. Both a web server and an executable version of the TAP score are available at http://protein.cribi.unipd.it/tap/. Conclusion: A novel procedure for energy normalization (TAP) has significantly improved the possibility to recognize the best experimental structures. It will allow the user to more reliably isolate problematic structures in the context of automated experimental structure determination. © 2007 Tosatto and Battistutta; licensee BioMed Central Ltd.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:36248964819,

title = {The PASTA server for protein aggregation prediction},

author = {Antonio Trovato and Flavio Seno and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-36248964819&origin=inward},

doi = {10.1093/protein/gzm042},

year  = {2007},

date = {2007-01-01},

journal = {Protein Engineering, Design and Selection},

volume = {20},

number = {10},

pages = {521-523},

abstract = {Many different proteins aggregate into amyloid fibrils characterized by cross-β structure. β-strands contributed by distinct protein molecules are generally found in a parallel in-register alignment. Here, we describe the web server for a novel algorithm, prediction of amyloid structure aggregation (PASTA), to predict the most aggregation-prone portions and the corresponding β-strand inter-molecular pairing for a given input sequence. PASTA was previously shown to yield results in excellent agreement with available experimental observations, when tested on both natively unfolded and structured proteins. The web server and downloadable source code are freely accessible from the URL: http://protein.cribi.unipd.it/pasta/. © The Author 2007. Published by Oxford University Press. All rights reserved.},

note = {Cited by: 213; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33845724178,

title = {The Thioredoxin Specificity of Drosophila GPx: A Paradigm for a Peroxiredoxin-like Mechanism of many Glutathione Peroxidases},

author = {Matilde Maiorino and Fulvio Ursini and Valentina Bosello and Stefano Toppo and Silvio C. E. Tosatto and Pierluigi Mauri and Katja Becker and Antonella Roveri and Cristiana Bulato and Louise Benazzi and Antonella De Palma and Leopold Flohé},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33845724178&origin=inward},

doi = {10.1016/j.jmb.2006.10.033},

year  = {2007},

date = {2007-01-01},

journal = {Journal of Molecular Biology},

volume = {365},

number = {4},

pages = {1033-1046},

publisher = {Academic Press},

abstract = {Some members of the glutathione peroxidase (GPx) family have been reported to accept thioredoxin as reducing substrate. However, the selenocysteine-containing ones oxidise thioredoxin (Trx), if at all, at extremely slow rates. In contrast, the Cys homolog of Drosophila melanogaster exhibits a clear preference for Trx, the net forward rate constant, k′+2, for reduction by Trx being 1.5 × 106 M- 1 s- 1, but only 5.4 M- 1 s- 1 for glutathione. Like other CysGPxs with thioredoxin peroxidase activity, Drosophila melanogaster (Dm)GPx oxidized by H2O2 contained an intra-molecular disulfide bridge between the active-site cysteine (C45; CP) and C91. Site-directed mutagenesis of C91 in DmGPx abrogated Trx peroxidase activity, but increased the rate constant for glutathione by two orders of magnitude. In contrast, a replacement of C74 by Ser or Ala only marginally affected activity and specificity of DmGPx. Furthermore, LC-MS/MS analysis of oxidized DmGPx exposed to a reduced Trx C35S mutant yielded a dead-end intermediate containing a disulfide between Trx C32 and DmGPx C91. Thus, the catalytic mechanism of DmGPx, unlike that of selenocysteine (Sec)GPxs, involves formation of an internal disulfide that is pivotal to the interaction with Trx. Hereby C91, like the analogous second cysteine in 2-cysteine peroxiredoxins, adopts the role of a "resolving" cysteine (CR). Molecular modeling and homology considerations based on 450 GPxs suggest peculiar features to determine Trx specificity: (i) a non-aligned second Cys within the fourth helix that acts as CR; (ii) deletions of the subunit interfaces typical of tetrameric GPxs leading to flexibility of the CR-containing loop. Based of these characteristics, most of the non-mammalian CysGPxs, in functional terms, are thioredoxin peroxidases. © 2006 Elsevier Ltd. All rights reserved.},

note = {Cited by: 107; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33749344929,

title = {Improving the quality of protein structure models by selecting from alignment alternatives},

author = {Ingolf Sommer and Stefano Toppo and Oliver Sander and Thomas Lengauer and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33749344929&origin=inward},

doi = {10.1186/1471-2105-7-364},

year  = {2006},

date = {2006-01-01},

journal = {BMC Bioinformatics},

volume = {7},

abstract = {Background: In the area of protein structure prediction, recently a lot of effort has gone into the development of Model Quality Assessment Programs (MQAPs). MQAPs distinguish high quality protein structure models from inferior models. Here, we propose a new method to use an MQAP to improve the quality of models. With a given target sequence and template structure, we construct a number of different alignments and corresponding models for the sequence. The quality of these models is scored with an MQAP and used to choose the most promising model. An SVM-based selection scheme is suggested for combining MQAP partial potentials, in order to optimize for improved model selection. Results: The approach has been tested on a representative set of proteins. The ability of the method to improve models was validated by comparing the MQAP-selected structures to the native structures with the model quality evaluation program TM-score. Using the SVM-based model selection, a significant increase in model quality is obtained (as shown with a Wilcoxon signed rank test yielding p-values below 10-15). The average increase in TMscore is 0.016, the maximum observed increase in TM-score is 0.29. Conclusion: In template-based protein structure prediction alignment is known to be a bottleneck limiting the overall model quality. Here we show that a combination of systematic alignment variation and modern model scoring functions can significantly improve the quality of alignment-based models. © 2006 Sommer et al; licensee BioMed Central Ltd.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33947324043,

title = {Align: A C++ class library and web server for rapid sequence alignment prototyping},

author = {Silvio C. E. Tosatto and Alessandro Albiero and Alessandra Mantovan and Carlo Ferrari and Eckart Bindewald and Stefano Toppo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33947324043&origin=inward},

doi = {10.2174/157016306780136754},

year  = {2006},

date = {2006-01-01},

journal = {Current Drug Discovery Technologies},

volume = {3},

number = {3},

pages = {167-173},

abstract = {Sequence alignment remains a fundamental tool in most tasks related to the prediction of protein sequence and structure. A C++ class library was developed to facilitate the rapid implementation of a variety of state-of-the-art pairwise sequence alignment techniques. These range from simple sequence to sequence to the advanced profile to profile alignments with optional secondary structure information. Suboptimal alignments, frequently used to estimate regions of confidence, can also be generated. The object oriented design facilitates rapid implementation, testing and extension of existing functionality. A simple web interface, which can also be useful in bioinformatics education, is also provided. Source code, online documentation and a prototypical web interface are freely accessible to academic users from the URL: http://protein.cribi.unipd. it/align/. A sample case study in the modelling of human Cytochrome P450 is discussed. © 2006 Bentham Science Publishers Ltd.},

note = {Cited by: 1},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33747868721,

title = {Spritz: A server for the prediction of intrinsically disordered regions in protein sequences using kernel machines},

author = {Alessandro Vullo and Oscar Bortolamil and Gianluca Pollastri and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33747868721&origin=inward},

doi = {10.1093/nar/gkl166},

year  = {2006},

date = {2006-01-01},

journal = {Nucleic Acids Research},

volume = {34},

number = {WEB. SERV. ISS.},

abstract = {Intrinsically disordered proteins have long stretches of their polypeptide chain, which do not adopt a single native structure composed of stable secondary and tertiary structure in the absence of binding partners. The prediction of intrinsically disordered regions in proteins from sequence is increasingly becoming of interest, as the presence of many such regions in the complete genome sequences are discovered and important functional roles are associated with them. We have developed a machine learning approach based on two support vector machines (SVM) to discriminate disordered regions from sequence. The SVM are trained and benchmarked on two sets, representing long and short disordered regions. A preliminary version of Spritz was shown to perform consistently well at the recent biannual CASP-6 experiment [Critical Assessment of Techniques for Protein Structure Prediction (CASP), 2004]. The fully developed Spritz method is freely available as a web server at http://distill.ucd.ie/spritz/ and http://protein.cribi.unipd.it/spritz/. © The Author 2006. Published by Oxford University Press. All rights reserved.},

note = {Cited by: 129; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33645817062,

title = {Large-scale prediction of protein structure and function from sequence},

author = {Silvio C. E. Tosatto and Toppo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33645817062&origin=inward},

doi = {10.2174/138161206777585238},

year  = {2006},

date = {2006-01-01},

journal = {Current Pharmaceutical Design},

volume = {12},

number = {17},

pages = {2067-2086},

abstract = {The identification of novel drug targets from genomic data involves the large-scale analysis of many protein sequences. Methods for automated structure and function prediction are an essential tool for this purpose. In this review we concentrate on the recent developments in the field of protein structure prediction and how these can be used to gain hints about the function of proteins. The current state-of-the-art is highlighted through recent community-wide experiments aimed at comparing different approaches. For structure prediction this allows the identification of key improvements to increase the crucial sequence to structure alignment needed for accurate models. Function prediction is a rapidly maturing field that is still being benchmarked. Definitions for protein function are presented and available methods, mostly concentrating on functional site descriptors and structural motifs, presented. © 2006 Bentham Science Publishers Ltd.},

note = {Cited by: 15},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:28144455425,

title = {Functional insights from the structural modelling of a small Fe-hydrogenase},

author = {Silvio C. E. Tosatto and Giorgio M. Giacometti and Giorgio Valle and Paola Costantini},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-28144455425&origin=inward},

doi = {10.1016/j.bbrc.2005.11.012},

year  = {2006},

date = {2006-01-01},

journal = {Biochemical and Biophysical Research Communications},

volume = {339},

number = {1},

pages = {277-283},

abstract = {Recently, a novel Fe-hydrogenase from a high rate of hydrogen producing Enterobacter cloacae strain IIT-BT08 was identified and partially characterized. This 147 residue protein was found to be much smaller than previously known Fe-hydrogenases, yet retaining a high catalytic activity. We predicted the structure of this protein and found it to be structurally similar to one of the two sub-domains containing the catalytic H-cluster so far jointly present in all other Fe-hydrogenases. This novel architecture allows a tentative explanation of protein function with the high rate of catalytic activity being due to a missing regulatory sub-domain, presumably allowing higher enzymatic activity at the cost of greater exposure to oxygen inactivation. This new insight may improve our understanding of the molecular and functional organization of other, more complex Fe-hydrogenases. © 2005 Elsevier Inc. All rights reserved.},

note = {Cited by: 12},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33747123661,

title = {Molecular characterization of large deletions in the von Hippel-Lindau (VHL) gene by quantitative real-time PCR: The hypothesis of an Alu-mediated mechanism underlying VHL gene rearrangements},

author = {Alberto Casarin and Maddalena Martella and Roberta Polli and Emanuela Leonardi and Laura Anesi and Alessandra Murgia},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33747123661&origin=inward},

doi = {10.1007/BF03256463},

year  = {2006},

date = {2006-01-01},

journal = {Molecular Diagnosis and Therapy},

volume = {10},

number = {4},

pages = {243-249},

publisher = {Adis International Ltd},

abstract = {Introduction: Mutations of the von Hippel-Lindau (VHL) gene are responsible for VHL disease. This is a familial autosomal-dominant syndrome, predisposing to the development of benign and malignant tumors, including CNS and retinal hemangioblastomas, pheochromocytomas, and clear cell renal carcinomas. At least 30% of the disease-causing mutations in the VHL gene involve large alterations. Identification of these mutations is not possible using PCR-based mutational scanning methods. Quantitative Southern blot analysis has been traditionally employed for the detection of complete or partial deletions and more complex rearrangements of the gene. Methods: An alternative quantitative method was developed using a combination of quantitative Southern blot analysis and real-time PCR. With this approach, we studied 24 large VHL gene alterations to determine the exact nature of the mutations and to possibly characterize the boundaries of the deleted regions. Results: This combined molecular approach showed that all the VHL alterations studied were due to deletions, from which the position in the gene could be more precisely mapped. One of the samples that was completely characterized was found to carry an intragenic 2.2kb deletion with both 5′ and 3′ breakpoints located within Alu-repeat sequences. Conclusion: This is the first report on the molecular analysis of large VHL alterations. The results of our study and the complete characterization of a large deletion lead to the hypothesis that an Alu-mediated mechanism may be responsible for the common occurrence of large alterations in the VHL gene. © 2006 Adis Data Information BV. All rights reserved.},

note = {Cited by: 24},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33645811319,

title = {Fine-grained statistical torsion angle potentials are effective in discriminating native protein structures},

author = {Alessandro Albiero and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33645811319&origin=inward},

doi = {10.2174/157016306776637591},

year  = {2006},

date = {2006-01-01},

journal = {Current Drug Discovery Technologies},

volume = {3},

number = {1},

pages = {75-81},

abstract = {Modelling of drug targets requires the reliable selection of an accurate and representative structure from large ensembles of alternate models. Statistical potentials developed to discriminate native protein structures generally represent pairwise interactions between atoms, which are less sensitive to local conformational details. The discrimination of local distortions is therefore particularly difficult. Local interaction preferences, expressed through torsion angles, are rarely used, as some controversy exists in the literature regarding their discrimination power. The present study aims to benchmark the efficiency of different implementations of torsion angle propensities for selecting the native structure from ensembles of well-constructed decoys. Several statistical potentials derived from fine-grained discretisations of torsion angle space are constructed and evaluated. Results from a comparison with nine widely used statistical scoring functions show the torsion angle potentials to be more effective in recognising native structures and to improve with the number of torsion angles considered. These data suggest local structural propensities to be important for estimating the overall quality of native-like models. © 2006 Bentham Science Publishers Ltd.},

note = {Cited by: 3},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:33644670813,

title = {Functional interaction of phospholipid hydroperoxide glutathione peroxidase with sperm mitochondrion-associated cysteine-rich protein discloses the adjacent cysteine motif as a new substrate of the selenoperoxidase},

author = {Matilde Maiorino and Antonella Roveri and Louise Benazzi and Valentina Bosello and Pierluigi Mauri and Stefano Toppo and Silvio C. E. Tosatto and Fulvio Ursini},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-33644670813&origin=inward},

doi = {10.1074/jbc.M505983200},

year  = {2005},

date = {2005-01-01},

journal = {Journal of Biological Chemistry},

volume = {280},

number = {46},

pages = {38395-38402},

abstract = {The mitochondrial capsule is a selenium- and disulfide-rich structure enchasing the outer mitochondrial membrane of mammalian spermatozoa. Among the proteins solubilized from the sperm mitochondrial capsule, we confirmed, by using a proteomic approach, the presence of phospholipid hydroperoxide glutathione peroxidase (PHGPx) as a major component, and we also identified the sperm mitochondrion-associated cysteine-rich protein (SMCP) and fragments/aggregates of specific keratins that previously escaped detection (Ursini, F., Heim, S., Kiess, M., Maiorino, M., Roveri, A., Wissing, J., and Flohé, L. (1999) Science 285, 1393-1396). The evidence for a functional association between PHGPx, SMCP, and keratins is further supported by the identification of a sequence motif of regularly spaced Cys-Cys doublets common to SMCP and high sulfur keratin-associated proteins, involved in bundling hair shaft keratin by disulfide cross-linking. Following the oxidative polymerization of mitochondrial capsule proteins, catalyzed by PHGPx, two-dimensional redox electrophoresis analysis showed homo- and heteropolymers of SMCP and PHGPx, together with other minor components. Adjacent cysteine residues in SMCP peptides are oxidized to cystine by PHGPx. This unusual disulfide is known to drive, by reshuffling oxidative protein folding. On this basis we propose that oxidative polymerization of the mitochondrial capsule is primed by the formation of cystine on SMCP, followed by reshuffling. Occurrence of reshuffling is further supported by the calculated thermodynamic gain of the process. This study suggests a new mechanism where selenium catalysis drives the cross-linking of structural elements of the cytoskeleton via the oxidation of a keratin-associated protein. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.},

note = {Cited by: 79; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:15244349255,

title = {Application of MM/PBSA colony free energy to loop decoy discrimination: Toward correlation between energy and root mean square deviation},

author = {Federico Fogolari and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-15244349255&origin=inward},

doi = {10.1110/ps.041004105},

year  = {2005},

date = {2005-01-01},

journal = {Protein Science},

volume = {14},

number = {4},

pages = {889-901},

abstract = {Accurate free energy estimation is needed in many predictive tasks. The molecular mechanics/Poisson-Boltzmann solvent accessible surface area (MM/PBSA) approach has proven to be accurate. However, the correlation between the estimated free energy and the distance (e.g., root mean square deviation [RMSD]) from the most stable conformation is hindered by the strong free energy dependence on minor conformational variations. In this paper, a protocol for MM/PBSA free energy estimation is designed and tested on several loop decoy sets. We show that further integration of MM/PBSA free energy estimator with the colony energy approach makes the correlation between the free energy and RMSD from the native structure apparent, for the test sets on which it could be applied. Our results suggest that (1) the MM/PBSA free energy estimator is able to detect native-like structures for most decoy sets, and (2) application of the colony energy approach greatly hampers the MM/energy strong dependence on minor conformational changes. Copyright © 2005 The Protein Society.},

note = {Cited by: 42; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:27544487034,

title = {Decomposing protein networks into domain-domain interactions},

author = {Mario Albrecht and Carola Huthmacher and Silvio C. E. Tosatto and Thomas Lengauer},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-27544487034&origin=inward},

doi = {10.1093/bioinformatics/bti1135},

year  = {2005},

date = {2005-01-01},

journal = {Bioinformatics},

volume = {21},

number = {SUPPL. 2},

publisher = {Oxford University Press},

abstract = {Summary: The application of novel experimental techniques has generated large networks of protein-protein interactions. Frequently, important information on the structure and cellular function of protein-protein interactions can be gained from the domains of interacting proteins. We have designed a Cytoscape plugin that decomposes interacting proteins into their respective domains and computes a putative network of corresponding domain-domain interactions. To this end, the network graph of proteins has been extended by additional node and edge types for domain interactions, including different node and edge shapes and coloring schemes used for visualization. An additional plugin provides supplementary web links to Internet resources on domain function and structure. © The Author 2005. Published by Oxford University Press. All rights reserved.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:29244479220,

title = {A decoy set for the thermostable subdomain from chicken villin headpiece, comparison of different free energy estimators},

author = {Federico Fogolari and Silvio C. E. Tosatto and Giorgio Colombo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-29244479220&origin=inward},

doi = {10.1186/1471-2105-6-301},

year  = {2005},

date = {2005-01-01},

journal = {BMC Bioinformatics},

volume = {6},

abstract = {Background: Estimators of free energies are routinely used to judge the quality of protein structural models. As these estimators still present inaccuracies, they are frequently evaluated by discriminating native or native-like conformations from large ensembles of so-called decoy structures. Results: A decoy set is obtained from snapshots taken from 5 long (100 ns) molecular dynamics (MD) simulations of the thermostable subdomain from chicken villin headpiece. An evaluation of the energy of the decoys is given using: i) a residue based contact potential supplemented by a term for the quality of dihedral angles; ii) a recently introduced combination of four statistical scoring functions for model quality estimation (FRST); iii) molecular mechanics with solvation energy estimated either according to the generalized Born surface area (GBSA) or iv) the Poisson-Boltzmann surface area (PBSA) method. Conclusions: The decoy set presented here has the following features which make it attractive for testing energy scoring functions: 1) it covers a broad range of RMSD values (from less than 2.0 Å to more than 12 Å); 2) it has been obtained from molecular dynamics trajectories, starting from different non-native-like conformations which have diverse behaviour, with secondary structure elements correctly or incorrectly formed, and in one case folding to a native-like structure. This allows not only for scoring of static structures, but also for studying, using free energy estimators, the kinetics of folding; 3) all structures have been obtained from accurate MD simulations in explicit solvent and after molecular mechanics (MM) energy minimization using an implicit solvent method. The quality of the covalent structure therefore does not suffer from steric or covalent problems. The statistical and physical effective energy functions tested on the set behave differently when native simulation snapshots are included or not in the set and when averaging over the trajectory is performed. © 2005 Fogolari et al., licensee BioMed Central Ltd.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:28144448406,

title = {The Victor/FRST function for model quality estimation},

author = {Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-28144448406&origin=inward},

doi = {10.1089/cmb.2005.12.1316},

year  = {2005},

date = {2005-01-01},

journal = {Journal of Computational Biology},

volume = {12},

number = {10},

pages = {1316-1327},

abstract = {Scoring functions are widely used in the final step of model selection in protein structure prediction. This is of interest both for comparative modeling targets, where it is important to select the best model among a set of many good, "correct" ones, as well as for other (fold recognition or novel fold) targets, where the set may contain many incorrect models. A novel combination of four knowledge-based potentials recognizing different features of native protein structures is introduced and tested. The pairwise, solvation, hydrogen bond, and torsion angle potentials contain largely orthogonal information. Of these, the torsion angle potential is found to show the strongest correlation with model quality. Combining these features with a linear weighting function, it was possible to construct a robust energy function capable of discriminating native-like structures on several benchmarking sets. In a recent blind test (CAFASP-4 MQAP), the scoring function ranked consistently well and was able to reliably distinguish the correct template from an ensemble of high quality decoys in 52 of 70 cases (33 of 34 for comparative modeling). An executable version of the Victor/FRST function for Linux PCs is available for download from the URL http://protein.cribi.unipd.it/frst/. © Mary Ann Liebert, Inc.},

note = {Cited by: 96},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:27744551994,

title = {Structural insights into the function of human caveolin 1},

author = {Enzo Spisni and Vittorio Tomasi and Alessandro Cestaro and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-27744551994&origin=inward},

doi = {10.1016/j.bbrc.2005.10.099},

year  = {2005},

date = {2005-01-01},

journal = {Biochemical and Biophysical Research Communications},

volume = {338},

number = {3},

pages = {1383-1390},

abstract = {Caveolin-1 (Cav-1) is emerging as the central protein controlling caveolae formation, caveolae trafficking, and cellular signalling. In particular, it is known that Cav-1 interacts and modulates the activity of several signalling proteins through the so-called caveolin scaffolding domain. In this paper, we used a bioinformatics approach to assess the validity of some long-standing structural features of Cav-1. We could confirm the existence of a membrane spanning region of Cav-1 and highlight an interesting pattern of palmitoylated cysteine residues explaining the structural features of the Cav-1 C-terminal region. Moreover, the scaffolding domain is predicted to have a different structure than previously reported. © 2005 Elsevier Inc. All rights reserved.},

note = {Cited by: 50},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:13844292778,

title = {The SSEA server for protein secondary structure alignment},

author = {Paolo Fontana and Eckart Bindewald and Stefano Toppo and Riccardo Velasco and Giorgio Valle and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-13844292778&origin=inward},

doi = {10.1093/bioinformatics/bti013},

year  = {2005},

date = {2005-01-01},

journal = {Bioinformatics},

volume = {21},

number = {3},

pages = {393-395},

publisher = {Oxford University Press},

abstract = {Summary: We present a web server that computes alignments of protein secondary structures. The server supports both performing pairwise alignments and searching a secondary structure against a library of domain folds. It can calculate global and local secondary structure element alignments. A combination of local and global alignment steps can be used to search for domains inside the query sequence or help in the discrimination of novel folds. Both the SCOP and PDB fold libraries, clustered at 95 and 40% sequence identity, are available for alignment. © Oxford University Press 2004; all rights reserved.},

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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:28944433027,

title = {Lys300 plays a major role in the catalytic mechanism of maize polyamine oxidase},

author = {Fabio Polticelli and Jaswir Basran and Carmen Faso and Alessandra Cona and Giovanni Minervini and Riccardo Angelini and Rodolfo Federico and Nigel S. Scrutton and Paraskevi Tavladoraki},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-28944433027&origin=inward},

doi = {10.1021/bi050983i},

year  = {2005},

date = {2005-01-01},

journal = {Biochemistry},

volume = {44},

number = {49},

pages = {16108-16120},

abstract = {Maize polyamine oxidase (MPAO) is a flavin adenine dinucleotide (FAD)-dependent enzyme that catalyses the oxidation of spermine and spermidine at the secondary amino groups. The structure of MPAO indicates a 30-Â long U-shaped tunnel that forms the catalytic site, with residues Glu62 and Glu170 located close to the enzyme-bound FAD and residue Tyr298 in close proximity to Lys300, which in turn is hydrogen-bonded to the flavin N5 atom via a water molecule (HOH309). To provide insight into the role of these residues in the catalytic mechanism of FAD reduction, we have performed steady-state and stopped-flow studies with wild-type, Glu62Gln, Glu170Gln, Tyr298Phe, and Lys300Met MPAO enzymes. We show that the steady-state enzyme activity is governed by an ionisable group with a macroscopic pKa of textasciitilde 5.8. Kinetic analysis of the Glu62Gln, Glu170Gln, and Tyr298Phe MPAO enzymes have indicated (i) only small perturbations in catalytic activity as a result of mutation and (ii) steady-state pH profiles essentially unaltered when compared to the wild-type enzyme, suggesting that these residues do not play a critical role in the reaction mechanism. These kinetic observations are consistent with computational calculations that suggest that Glu62 and Glu170 are protonated over the pH range accessible to kinetic studies. Substitution of Lys300 with Met in MPAO resulted in a 1400-fold decrease in the rate of flavin reduction and a 160-fold decrease in the equilibrium dissociation constant for the Lys300Met- spermidine complex, consistent with a major role for this residue in the mechanism of substrate oxidation. A sizable solvent isotope effect (SIE = 5) accompanies FAD reduction in the wild-type enzyme and steady-state turnover (SIE = 2.3) of MPAO, consistent with the reductive half-reaction of MPAO making a major contribution to rate limitation in steady-state turnover. Studies using the enzyme-monitored turnover method indicate that oxidized FAD is the prominent form during steady-state turnover, consistent with the reductive half-reaction being rate-limiting. Our studies indicate the importance of Lys300 and probable importance of HOH309 to the mechanism of flavin reduction in MPAO. Possible roles for Lys300 and water in the mechanism of flavin reduction are discussed. © 2005 American Chemical Society.},

note = {Cited by: 45},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:22244489070,

title = {A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment},

author = {Del Castillo and Rodríguez-Ballesteros and Álvarez and Hutchin and Leonardi and De Oliveira and Azaiez and Brownstein and Avenarius and Marlin and Pandya and Shahin and Siemering and Weil and Wuyts and Aguirre and Marlín and Moreno-Pelayo and Villamar and Avraham and Dahl and Kanaan and Nance and Petit and Smith and Van Camp and Sartorato and Murgia and Moreno and Ignacio Del Castillo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-22244489070&origin=inward},

doi = {10.1136/jmg.2004.028324},

year  = {2005},

date = {2005-01-01},

journal = {Journal of Medical Genetics},

volume = {42},

number = {7},

pages = {588-594},

abstract = {DFNB1 deafness, caused by mutations in the gene encoding connexin-26 (GJB2), is the most frequent subtype of autosomal recessive non-syndromic hearing impairment. Molecular testing for GJB2 mutations has become a standard diagnostic approach for subjects with this disorder. However, 10-50% of affected subjects with GJB2 mutations carry only one mutant allele. A 309 kb deletion truncating the GJB6 gene (encoding connexin-30) was shown to be the accompanying mutation in up to 50% of deaf GJB2 heterozygotes in different populations. We report the molecular characterisation of the breakpoint junction of a novel 232 kb deletion in the DFNB1 locus, del(GJB6-D13S1854), which was also found in trans with pathogenic GJB2 mutations in affected subjects. The deletion arose by unequal homologous recombination, involving an AluY sequence inside GJB6 intron 2, a mechanism which might generate other deletions at DFNB1. We developed a novel diagnostic test for the combined detection of del(GJB6-D13S1830) and this new del(GJB6-D13S1854) in a single PCR assay. The del(GJB6-D13S1854) mutation accounts for 25.5% of the affected GJB2 heterozygotes which remained unresolved after screening for del(GJB6-D13S1830) in Spain, 22.2% in the UK, 6.3% in Brazil and 1.9% in northern Italy. It was not found in affected GJB2 heterozygotes from France, Belgium, Israel, the Palestinian Authority, USA, or Australia. Haplotype analysis revealed a common founder for the mutation in Spain, Italy, and the UK. Our data further support the complexity the genetic epidemiology of non-syndromic hearing impairment.},

note = {Cited by: 272; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:12144287717,

title = {A genotype-phenotype correlation for GJB2 (connexin 26) deafness},

author = {Cryns and Orzan and Murgia and Huygen and Moreno and Del Castillo and Parker Chamberlin and Azaiez and Prasad and Cucci and Leonardi and Snoeckx and Govaerts and Van De Heyning and Van De Heyning and Smith and Van Camp},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-12144287717&origin=inward},

doi = {10.1136/jmg.2003.013896},

year  = {2004},

date = {2004-01-01},

journal = {Journal of Medical Genetics},

volume = {41},

number = {3},

pages = {147-154},

publisher = {BMJ Publishing Group},

abstract = {Introduction: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. Objective: To assess a possible genotype-phenotype correlation for GJB2. Design: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. Subjects: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. Results: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. Conclusions: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.},

note = {Cited by: 191; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:0042379959,

title = {Simple consensus procedures are effective and sufficient in secondary structure prediction},

author = {Mario Albrecht and Silvio C. E. Tosatto and Thomas Lengauer and Giorgio Valle},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-0042379959&origin=inward},

doi = {10.1093/protein/gzg063},

year  = {2003},

date = {2003-01-01},

journal = {Protein Engineering},

volume = {16},

number = {7},

pages = {459-462},

publisher = {Oxford University Press},

abstract = {We have analyzed the performance of majority voting on minimal combination sets of three state-of-the-art secondary structure prediction methods in order to obtain a consensus prediction. Using three large benchmark sets from the EVA server, our results show a significant improvement in the average Q3 prediction accuracy of up to 1.5 percentage points by consensus formation. The application of an additional trivial filtering procedure for predicted secondary structure elements that are too short, does not significantly affect the prediction accuracy. Our analysis also provides valuable insight into the similarity of the results of the prediction methods that we combine as well as the higher confidence in consistently predicted secondary structure.},

note = {Cited by: 67; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:0038270170,

title = {Connexin 26 35delG does not represent a mutational hotspot},

author = {Caryn R. Rothrock and Alessandra Murgia and Edi L. Sartorato and Emanuela Leonardi and Sainan Wei and Sarah L. Lebeis and Laura E. Yu and Jill L. Elfenbein and Rachel A. Fisher and Karen H. Friderici},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-0038270170&origin=inward},

doi = {10.1007/s00439-003-0944-2},

year  = {2003},

date = {2003-01-01},

journal = {Human Genetics},

volume = {113},

number = {1},

pages = {18-23},

publisher = {Springer Verlag},

abstract = {Non-syndromic hearing impairment (NSHI) is the most common form of deafness and presents with no other symptoms or sensory defects. Mutations in the gap junction gene GJB2 account for a high proportion of recessive NSHI. The GJB2 gene encodes connexin 26, which forms plasma membrane channels between cochlear cells. In Caucasian populations a single mutation, 35delG, accounts for most cases of NSHI. This mutation appears to be most prevalent in individuals of Mediterranean European descent, with carrier frequencies estimated as being as high as one in thirty. The 35delG region may be a mutational hotspot. The mutation arises from the deletion of a guanine from a six-guanine stretch and nearby microsatellite markers show little evidence for linkage disequilibrium. We believe that 35delG is an old mutation in a chromosomal region of high recombination. The genetic context of the 35delG mutation was examined to distinguish between an old or a recurring mutation. We identified two single-nucleotide polymorphisms (SNPs) immediately upstream of the first exon of GJB2. Polymerase chain reaction/restriction fragment length polymorphism analysis determined the SNP genotype of 35delG containing chromosomes from various populations, including Italy, Brazil, and North America. We found the same, relatively rare, polymorphism associated with the 35delG mutation in all populations studied. We have also examined microsatellite markers D13S175, which is 80kb telomeric to GJB2, and D13S1316, which is 80kb centromeric to GJB2. D13S175 appears to be in weak linkage disequilibrium with 35delG, while D13S1316 is less so. SNPs located between the 35delG mutation and the microsatellite markers show strong evidence of linkage disequilibrium. Taken together, these results indicate there has been substantial recombination near the 35delG mutation; however, we present evidence that the 35delG mutation arose in European and Middle Eastern populations from a single mutational event on a founder chromosome. © Springer-Verlag 2003.},

note = {Cited by: 48},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:0345600222,

title = {MANIFOLD: Protein fold recognition based on secondary structure, sequence similarity and enzyme classification},

author = {Eckart Bindewald and Alessandro Cestaro and Jürgen Hesser and Matthias Heiler and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-0345600222&origin=inward},

doi = {10.1093/protein/gzg106},

year  = {2003},

date = {2003-01-01},

journal = {Protein Engineering},

volume = {16},

number = {11},

pages = {785-789},

publisher = {Oxford University Press},

abstract = {We present a protein fold recognition method, MANIFOLD, which uses the similarity between target and template proteins in predicted secondary structure, sequence and enzyme code to predict the fold of the target protein. We developed a non-linear ranking scheme in order to combine the scores of the three different similarity measures used. For a difficult test set of proteins with very little sequence similarity, the program predicts the fold class correctly in 34% of cases. This is an over twofold increase in accuracy compared with sequence-based methods such as PSI-BLAST or GenTHREADER, which score 13-14% correct first hits for the same test set. The functional similarity term increases the prediction accuracy by up to 3% compared with using the combination of secondary structure similarity and PSI-BLAST alone. We argue that using functional and secondary structure information can increase the fold recognition beyond sequence similarity.},

note = {Cited by: 35},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:0036096608,

title = {A divide and conquer approach to fast loop modeling},

author = {Silvio C. E. Tosatto and Eckart Bindewald and Jürgen Hesser and Reinhard Männer},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-0036096608&origin=inward},

doi = {10.1093/protein/15.4.279},

year  = {2002},

date = {2002-01-01},

journal = {Protein Engineering},

volume = {15},

number = {4},

pages = {279-286},

publisher = {Oxford University Press},

abstract = {We describe a fast ab initio method for modeling local segments in protein structures. The algorithm is based on a divide and conquer approach and uses a database of precalculated look-up tables, which represent a large set of possible conformations for loop segments of variable length. The target loop is recursively decomposed until the resulting conformations are small enough to be compiled analytically. The algorithm, which is not restricted to any specific loop length, generates a ranked set of loop conformations in 20-180 s on a desktop PC. The prediction quality is evaluated in terms of global RMSD. Depending on loop length the top prediction varies between 1.06 Å RMSD for three-residue loops and 3.72 Å RMSD for eight-residue loops. Due to its speed the method may also be useful to generate alternative starting conformations for complex simulations.},

note = {Cited by: 63; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:0032727332,

title = {Cx26 deafness: Mutation analysis and clinical variability},

author = {Murgia and Orzan and Polli and Martella and Vinanzi and Leonardi and Arslan and Zacchello},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-0032727332&origin=inward},

doi = {10.1136/jmg.36.11.829},

year  = {1999},

date = {1999-01-01},

journal = {Journal of Medical Genetics},

volume = {36},

number = {11},

pages = {829-832},

publisher = {BMJ Publishing Group},

abstract = {Mutations in the gap junction protein connexin 26 (Cx26) gene (GJB2) seem to account for many cases of congenital sensorineural hearing impairment, the reported prevalence being 34-50% in autosomal recessive cases and 10-37% in sporadic cases. The hearing impairment in these patients has been described as severe or profound. We have studied 53 unrelated subjects with congenital non-syndromic sensorineural hearing impairment in order to evaluate the prevalence and type of Cx26 mutations and establish better genotype-phenotype correlation. Mutations in the Cx26 gene were found in 53% of the subjects tested, 35.3% of the autosomal recessive and 60% of the sporadic cases in our series. Three new mutations were identified. The hearing deficit varied from mild to profound even in 35delG homozygotes within the same family. No evidence of progression of the impairment was found. Alterations of the Cx26 gene account for a large proportion of cases of congenital non-syndromic sensorineural deafness, so it seems appropriate to extend the molecular analysis even to subjects with mild or moderate prelingual hearing impairment of unknown cause.},

note = {Cited by: 127; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}