Systematic Functional Prioritization of Protein Posttranslational Modifications

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94107, USA.
Cell (Impact Factor: 32.24). 07/2012; 150(2):413-25. DOI: 10.1016/j.cell.2012.05.036
Source: PubMed


Protein function is often regulated by posttranslational modifications (PTMs), and recent advances in mass spectrometry have resulted in an exponential increase in PTM identification. However, the functional significance of the vast majority of these modifications remains unknown. To address this problem, we compiled nearly 200,000 phosphorylation, acetylation, and ubiquitination sites from 11 eukaryotic species, including 2,500 newly identified ubiquitylation sites for Saccharomyces cerevisiae. We developed methods to prioritize the functional relevance of these PTMs by predicting those that likely participate in cross-regulatory events, regulate domain activity, or mediate protein-protein interactions. PTM conservation within domain families identifies regulatory "hot spots" that overlap with functionally important regions, a concept that we experimentally validated on the HSP70 domain family. Finally, our analysis of the evolution of PTM regulation highlights potential routes for neutral drift in regulatory interactions and suggests that only a fraction of modification sites are likely to have a significant biological role.

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Available from: Veronique Albanese
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    • "The seven acetylation sites identified here also align along the dimer interface in the ATP state, implying that they combine with the phosphosite for signal propagation. These hydrogen-bonding interactions provide a rationale for increased dimerization of Hsp70 Sf9 and the conservation of the phosphosite (Beltrao et al., 2012), and the correspondence of the amino acid residues involved in acetylation ( in eukaryotes suggests their functional relevance in vivo. "
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