UniProt release 2012_03
Published March 21, 2012
The importance of being manual
Manual annotation is a time-consuming and expensive process, but undoubtedly adds great value to knowledgebases like UniProtKB. A recent and very elegant study on sirtuin-5 illustrates how new functions continue to be discovered within what are thought to be well characterized protein families. Curating this information facilitates its dissemination as well as its subsequent (re)use in automatic annotation and function prediction systems.
Sirtuins, also called Sir2 proteins, are NAD-dependent deacetylases that regulate important biological processes. The name ‘Sir2’ comes from the yeast ‘silent information regulation 2’ gene, a gene involved among others in transcriptional repression. Sirtuins belong to a family of evolutionally conserved proteins occurring in all kingdoms. Mammals have seven sirtuins, SIRT1 to SIRT7. Robust deacetylase activity has been demonstrated for mammalian SIRT1 to SIRT3 and the annotation concerning this potential function has been propagated to other paralogues on the basis of their sequence similarity. However, so far SIRT4 to SIRT7 have been shown to have only a very weak deacetylase activity, if any. While this could be due to an inappropriate choice of peptides for the analysis, it could also be envisioned that their physiological activity is different.
A major breakthrough in the field came from the study of SIRT5 crystal structure. It appeared that the pocket used by SIRT2 to host acetyl groups was much larger in SIRT5, large enough to host a negatively charged acyl group instead. The most common acyl-CoA molecules with a carboxylate group in cells are malonyl-CoA and succinyl-CoA. Hence, malonyl-and succinyl-peptides were produced and tested as substrates for SIRT5. Goal! SIRT5 was actually able to catalyze their hydrolysis, proving it is a desuccinylase and a demalonylase, rather than a deacetylase. This discovery raised another question: do such post-translational modifications (PTMs) exist at all? Lysine succinylation has been shown on E.coli homoserine trans-succinylase, but not on mammalian proteins, and lysine malonylation had never been reported.
The presence of these PTMs was investigated in mitochondria, the organelle hosting SIRT5. Goal! Several proteins were found to be either succinylated or malonylated or both. Among them is CPS1 whose activity has been previously shown to be regulated by SIRT5.
Cross-references to DNASU
Cross-references have been added to DNASU, a plasmid repository providing centralized archival and distribution of over 131,000 plasmids and empty vectors, including over 45,000 plasmids containing more than 7,000 human genes.
DNASU is available at http://dnasu.asu.edu
The format of the explicit links in the flat file is:
|Resource identifier||DNASU identifier|
DR DNASU; 1400; -.
Changes to keywordsNew keyword:
Changes to the controlled vocabulary for PTMsNew term for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):
- Methionine sulfoxide