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UniProt release 2010_10

Published October 5, 2010

UniProtKB/Swiss-Prot ubiquitin pathway annotation

Post-translational modifications (PTMs) can have a profound effect on protein function. They act as switches to activate or inactivate polypeptides, change their subcellular location, modify protein-protein partnerships, etc. However, no PTM is as versatile as ubiquitination, i.e. the post-translational conjugation of ubiquitin. Ubiquitination can occur on a large range of proteins and not only controls their lifespan, but also expands their functional repertoire (see reviews). In view of its importance in many cellular events, we have decided to qualitatively and quantitatively improve our annotation of proteins involved in the ubiquitin and ubiquitin-like pathways in various species, ranging from plants to mammals. Bacteria and archaea which have been recently shown to have an ubiquitin-like system for protein degradation, called pupylation, were not neglected (see next release’s headline).

Ubiquitin (see for instance entry P0CG47 featuring one of the human ubiquitin gene products) is a small 76 amino-acid protein that is ubiquitously expressed (hence its name) in all eukaryotic cells and highly conserved among eukaryotic species: human and yeast ubiquitin share 96% sequence identity. Ubiquitination most frequently occurs via an isopeptide bond between a lysine of the target protein and the C-terminal glycine of ubiquitin. Substrates can be monoubiquitinated, via the attachment of a single ubiquitin, or multiubiquitinated, when more than one amino acid is modified with monoubiquitin. Ubiquitin can also be added sequentially to substrates to form ubiquitin chains resulting in polyubiquitination. In ubiquitin polymers, the lysine side chain of one ubiquitin molecule is linked to the C terminus of another ubiquitin molecule, and so on. Ubiquitin contains 7 lysine residues, all of which can contribute to such linkages with a different functional outcome for the target protein. For instance the most prominent function of ubiquitin is labeling proteins for proteasomal degradation. This signal is conveyed by polyubiquitin chains linked through the ubiquitin lysine-48 side chain (‘Lys-48’-linked chains). ‘Lys-63’-linked polyubiquitin chain functions in signal transduction and DNA repair without functioning as a degradation signal. Monoubiquitination has recently been shown to have a signaling function in the endocytic pathway.

Three types of enzyme – E1, E2 and E3 – carry out ubiquitination. E1s activate ubiquitin, E2s pick up the ubiquitin from E1 and, in close collaboration with E3, conjugate it to substrates. E3s have a crucial role in recognition of the substrate. They are either catalytically active and directly transfer the activated ubiquitin to the target, or serve as a scaffold linking catalytic E2 to the appropriate substrate. All eukaryotes encode a very limited number of E1 enzymes (a single gene in many species, 3 in humans), but multiple isozymes of E2 and E3, up to several dozen E2s and many hundreds of E3s. This allows the modification of many proteins in a highly specific and controlled manner.

Ubiquitin modification is only transient: enzymes, known as deubiquitinating enzymes (DUBs), can remove ubiquitin molecules that are attached to proteins. They also show specificity towards the type of ubiquitin linkage. For instance, the BRCC3 metalloprotease specifically cleaves ‘Lys-63’-linked polyubiquitin chains, while the cysteine protease USP15 shows preference for ‘Lys-48’ chains.

The ubiquitin pathway turned out to be even more complex with the discovery of several ubiquitin-like proteins, including SUMO, ISG15, NEDD8, UFM1. These proteins also regulate a vast array of cellular events, such as nuclear transport, transcriptional regulation, apoptosis, protein stability, signalling, protein-protein interactions, etc.

The UniProtKB annotation marathon led to the integration of 940 new eukaryotic entries and annotation of 942 new sites of ubiquitination. Close to 4’000 experimental GO terms have been manually added to UniProtKB entries. 469 proteins directly involved in the process of ubiquitination (and ubiquitin-like conjugation) have been annotated or updated and can now be retrieved with the keyword ‘Ubl conjugation pathway’, along with some other 3’400 manually reviewed entries. Proteins undergoing ubiquitination, including autoubiquitination classically observed in E3 proteins, are tagged with the keyword ‘Ubl conjugation’ and, when known, the effect of the PTM is indicated in the ‘Post-translational modification’ subsection of ‘General Annotation’ (see for instance entry Q9Y243).

UniProtKB News

Changes to cross-references to Ensembl

The cross-references to the Ensembl database have been modified. The optional field describing the species name has been removed, because it is no longer necessary to build a valid URL.

Example:

Previous format in the flat file:

DR   Ensembl; ENST00000220809; ENSP00000220809; ENSG00000104368; Homo sapiens.

New format:

DR   Ensembl; ENST00000220809; ENSP00000220809; ENSG00000104368.