Post-translational modifications: a challenge for proteomics and bioinformatics.
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Computational Biology↗
Biomedical subjects
Amos Bairoch
Publications and source records attributed to Amos Bairoch.
Protein sequence databases.
A variety of protein sequence databases exist, ranging from simple sequence repositories, which store data with little or no manual intervention in the creation of the records, to expertly curated universal databases that cover all species and in which the original sequence data are enhanced by the manual addition of further information in each sequence record. As the focus of researchers moves from the genome to the proteins encoded by it, these databases will play an even more important role as central comprehensive resources of protein information. Several the leading protein sequence databases are discussed here, with special emphasis on the databases now provided by the Universal Protein Knowledgebase (UniProt) consortium.
Animals↗
Swiss-Prot: juggling between evolution and stability.
We describe some of the aspects of Swiss-Prot that make it unique, explain what are the developments we believe to be necessary for the database to continue to play its role as a focal point of protein knowledge, and provide advice pertinent to the development of high-quality knowledge resources on one aspect or the other of the life sciences.
Amino Acid Sequence↗
[From genome to proteome--aim of human proteomics].
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Animals↗
ExPASy: The proteomics server for in-depth protein knowledge and analysis.
The ExPASy (the Expert Protein Analysis System) World Wide Web server (http://www.expasy.org), is provided as a service to the life science community by a multidisciplinary team at the Swiss Institute of Bioinformatics (SIB). It provides access to a variety of databases and analytical tools dedicated to proteins and proteomics. ExPASy databases include SWISS-PROT and TrEMBL, SWISS-2DPAGE, PROSITE, ENZYME and the SWISS-MODEL repository. Analysis tools are available for specific tasks relevant to proteomics, similarity searches, pattern and profile searches, post-translational modification prediction, topology prediction, primary, secondary and tertiary structure analysis and sequence alignment. These databases and tools are tightly interlinked: a special emphasis is placed on integration of database entries with related resources developed at the SIB and elsewhere, and the proteomics tools have been designed to read the annotations in SWISS-PROT in order to enhance their predictions. ExPASy started to operate in 1993, as the first WWW server in the field of life sciences. In addition to the main site in Switzerland, seven mirror sites in different continents currently serve the user community.
Databases, Protein↗
The InterPro Database, 2003 brings increased coverage and new features.
InterPro, an integrated documentation resource of protein families, domains and functional sites, was created in 1999 as a means of amalgamating the major protein signature databases into one comprehensive resource. PROSITE, Pfam, PRINTS, ProDom, SMART and TIGRFAMs have been manually integrated and curated and are available in InterPro for text- and sequence-based searching. The results are provided in a single format that rationalises the results that would be obtained by searching the member databases individually. The latest release of InterPro contains 5629 entries describing 4280 families, 1239 domains, 95 repeats and 15 post-translational modifications. Currently, the combined signatures in InterPro cover more than 74% of all proteins in SWISS-PROT and TrEMBL, an increase of nearly 15% since the inception of InterPro. New features of the database include improved searching capabilities and enhanced graphical user interfaces for visualisation of the data. The database is available via a webserver (http://www.ebi.ac.uk/interpro) and anonymous FTP (ftp://ftp.ebi.ac.uk/pub/databases/interpro).
Animals↗
The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003.
The SWISS-PROT protein knowledgebase (http://www.expasy.org/sprot/ and http://www.ebi.ac.uk/swissprot/) connects amino acid sequences with the current knowledge in the Life Sciences. Each protein entry provides an interdisciplinary overview of relevant information by bringing together experimental results, computed features and sometimes even contradictory conclusions. Detailed expertise that goes beyond the scope of SWISS-PROT is made available via direct links to specialised databases. SWISS-PROT provides annotated entries for all species, but concentrates on the annotation of entries from human (the HPI project) and other model organisms to ensure the presence of high quality annotation for representative members of all protein families. Part of the annotation can be transferred to other family members, as is already done for microbes by the High-quality Automated and Manual Annotation of microbial Proteomes (HAMAP) project. Protein families and groups of proteins are regularly reviewed to keep up with current scientific findings. Complementarily, TrEMBL strives to comprise all protein sequences that are not yet represented in SWISS-PROT, by incorporating a perpetually increasing level of mostly automated annotation. Researchers are welcome to contribute their knowledge to the scientific community by submitting relevant findings to SWISS-PROT at swiss-prot@expasy.org.
Animals↗
Automated annotation of microbial proteomes in SWISS-PROT.
Large-scale sequencing of prokaryotic genomes demands the automation of certain annotation tasks currently manually performed in the production of the SWISS-PROT protein knowledgebase. The HAMAP project, or 'High-quality Automated and Manual Annotation of microbial Proteomes', aims to integrate manual and automatic annotation methods in order to enhance the speed of the curation process while preserving the quality of the database annotation. Automatic annotation is only applied to entries that belong to manually defined orthologous families and to entries with no identifiable similarities (ORFans). Many checks are enforced in order to prevent the propagation of wrong annotation and to spot problematic cases, which are channelled to manual curation. The results of this annotation are integrated in SWISS-PROT, and a website is provided at http://www.expasy.org/sprot/hamap/.
Amino Acid Sequence↗
The PROSITE database, its status in 2002.
PROSITE [Bairoch and Bucher (1994) Nucleic Acids Res., 22, 3583-3589; Hofmann et al. (1999) Nucleic Acids Res., 27, 215-219] is a method of identifying the functions of uncharacterized proteins translated from genomic or cDNA sequences. The PROSITE database (http://www.expasy.org/prosite/) consists of biologically significant patterns and profiles designed in such a way that with appropriate computational tools it can rapidly and reliably help to determine to which known family of proteins (if any) a new sequence belongs, or which known domain(s) it contains.
Amino Acid Motifs↗
The application of bioinformatics to mass spectrometry.
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Calibration↗
FindPept, a tool to identify unmatched masses in peptide mass fingerprinting protein identification.
FindPept (http://www.expasy.org/tools/findpept.html) is a software tool designed to identify the origin of peptide masses obtained by peptide mass fingerprinting which are not matched by existing protein identification tools. It identifies masses resulting from unspecific proteolytic cleavage, missed cleavage, protease autolysis or keratin contaminants. It also takes into account post-translational modifications derived from the annotation of the SWISS-PROT database or supplied by the user, and chemical modifications of peptides. Based on a number of experimental examples, we show that the commonly held rules for the specificity of tryptic cleavage are an oversimplification, mainly because of effects of neighboring residues, experimental conditions, and contaminants present in the enzyme sample.
Algorithms↗
InterPro: an integrated documentation resource for protein families, domains and functional sites.
The exponential increase in the submission of nucleotide sequences to the nucleotide sequence database by genome sequencing centres has resulted in a need for rapid, automatic methods for classification of the resulting protein sequences. There are several signature and sequence cluster-based methods for protein classification, each resource having distinct areas of optimum application owing to the differences in the underlying analysis methods. In recognition of this, InterPro was developed as an integrated documentation resource for protein families, domains and functional sites, to rationalise the complementary efforts of the individual protein signature database projects. The member databases - PRINTS, PROSITE, Pfam, ProDom, SMART and TIGRFAMs - form the InterPro core. Related signatures from each member database are unified into single InterPro entries. Each InterPro entry includes a unique accession number, functional descriptions and literature references, and links are made back to the relevant member database(s). Release 4.0 of InterPro (November 2001) contains 4,691 entries, representing 3,532 families, 1,068 domains, 74 repeats and 15 sites of post-translational modification (PTMs) encoded by different regular expressions, profiles, fingerprints and hidden Markov models (HMMs). Each InterPro entry lists all the matches against SWISS-PROT and TrEMBL (2,141,621 InterPro hits from 586,124 SWISS-PROT and TrEMBL protein sequences). The database is freely accessible for text- and sequence-based searches.
Algorithms↗
PROSITE: a documented database using patterns and profiles as motif descriptors.
Among the various databases dedicated to the identification of protein families and domains, PROSITE is the first one created and has continuously evolved since. PROSITE currently consists of a large collection of biologically meaningful motifs that are described as patterns or profiles, and linked to documentation briefly describing the protein family or domain they are designed to detect. The close relationship of PROSITE with the SWISS-PROT protein database allows the evaluation of the sensitivity and specificity of the PROSITE motifs and their periodic reviewing. In return, PROSITE is used to help annotate SWISS-PROT entries. The main characteristics and the techniques of family and domain identification used by PROSITE are reviewed in this paper.
Amino Acid Motifs↗
High-quality protein knowledge resource: SWISS-PROT and TrEMBL.
SWISS-PROT is a curated protein sequence database which strives to provide a high level of annotation (such as the description of the function of a protein, its domain structure, post-translational modifications, variants, etc.), a minimal level of redundancy and a high level of integration with other databases. Together with its automatically annotated supplement TrEMBL, it provides a comprehensive and high-quality view of the current state of knowledge about proteins. Ongoing developments include the further improvement of functional and automatic annotation in the databases including evidence attribution with particular emphasis on the human, archaeal and bacterial proteomes and the provision of additional resources such as the International Protein Index (IPI) and XML format of SWISS-PROT and TrEMBL to the user community.
Amino Acid Sequence↗
The Sulfinator: predicting tyrosine sulfation sites in protein sequences.
UNLABELLED: Protein tyrosine sulfation is an important post-translational modification of proteins that go through the secretory pathway. No clear-cut acceptor motif can be defined that allows the prediction of tyrosine sulfation sites in polypeptide chains. The Sulfinator is a software tool that can be used to predict tyrosine sulfation sites in protein sequences with an overall accuracy of 98%. Four different Hidden Markov Models were constructed, each of them specialized to recognize sulfated tyrosine residues depending on their location within the sequence: near the N-terminus, near the C-terminus, in the center of a window with a size of at least 25 amino acids, as well as in windows containing several tyrosine residues. AVAILABILITY: The Sulfinator is accessible at (http://www.expasy.org/tools/sulfinator/). SUPPLEMENTARY INFORMATION: Sulfinator documentation is accessible at (http://www.expasy.org/tools/sulfinator/sulfinator-doc.html).
Amino Acid Sequence↗
ScanProsite: a reference implementation of a PROSITE scanning tool.
Many different software tools are available publicly to scan the PROSITE database of protein families. However, none of them, to our knowledge, wholly implements the PROSITE syntax, or satisfies all the rules for scanning a pattern against a sequence. We hereby propose a strict definition of how a PROSITE pattern is to be scanned against a sequence, and provide a reference implementation of a tool to scan PROSITE patterns, rules and profiles against protein sequences.
Computational Biology↗