title: Peptidase specificity from the substrate cleavage collection in the MEROPS database and a tool to measure cleavage site conservation.
abstract: One peptidase can usually be distinguished from another biochemically by its action on proteins, peptides and synthetic substrates. Since 1996, the MEROPS database (http://merops.sanger.ac.uk) has accumulated a collection of cleavages in substrates that now amounts to 66,615 cleavages. The total number of peptidases for which at least one cleavage is known is 1700 out of a total of 2457 different peptidases. This paper describes how the cleavages are obtained from the scientific literature, how they are annotated and how cleavages in peptides and proteins are cross-referenced to entries in the UniProt protein sequence database. The specificity profiles of 556 peptidases are shown for which ten or more substrate cleavages are known. However, it has been proposed that at least 40 cleavages in disparate proteins are required for specificity analysis to be meaningful, and only 163 peptidases (6.6%) fulfil this criterion. Also described are the various displays shown on the website to aid with the understanding of peptidase specificity, which are derived from the substrate cleavage collection. These displays include a logo, distribution matrix, and tables to summarize which amino acids or groups of amino acids are acceptable (or not acceptable) in each substrate binding pocket. For each protein substrate, there is a display to show how it is processed and degraded. Also described are tools on the website to help with the assessment of the physiological relevance of cleavages in a substrate. These tools rely on the hypothesis that a cleavage site that is conserved in orthologues is likely to be physiologically relevant, and alignments of substrate protein sequences are made utilizing the UniRef50 database, in which in each entry sequences are 50% or more identical. Conservation in this case means substitutions are permitted only if the amino acid is known to occupy the same substrate binding pocket from at least one other substrate cleaved by the same peptidase.
authors.affiliation: Wellcome Trust Sanger Institute and the EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. Electronic address: ndr@ebi.ac.uk.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Rawlings
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D055162:Biocatalysis; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D020407:Internet; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000145:classification / Q000378:metabolism*; D059748:Proteolysis; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D015203:Reproducibility of Results; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D020543:Proteome; D010447:Peptide Hydrolases
keywords: Binding pocket; Cleavage; Peptidase; Scissile bond; Specificity; Substrate