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Systematic functional prioritization of protein posttranslational modifications.

Cell | Jul 20, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22817900

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.

Pubmed ID: 22817900 RIS Download

Mesh terms: Acetylation | Amino Acid Sequence | Animals | Eukaryota | HSP70 Heat-Shock Proteins | Humans | Models, Molecular | Molecular Sequence Data | Phosphorylation | Protein Interaction Domains and Motifs | Protein Processing, Post-Translational | Protein Structure, Tertiary | Saccharomyces cerevisiae | Sequence Alignment | Ubiquitination

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Associated grants

  • Agency: NIAID NIH HHS, Id: AI090935
  • Agency: NIH HHS, Id: DP5 OD009180
  • Agency: NIH HHS, Id: DP5 OD009180
  • Agency: NIGMS NIH HHS, Id: GM062583
  • Agency: NIGMS NIH HHS, Id: GM081879
  • Agency: NIGMS NIH HHS, Id: GM082250
  • Agency: NIGMS NIH HHS, Id: GM084279
  • Agency: NIGMS NIH HHS, Id: GM084448
  • Agency: NIGMS NIH HHS, Id: GM55040
  • Agency: NIGMS NIH HHS, Id: GM56433
  • Agency: NIAID NIH HHS, Id: P01 AI090935
  • Agency: NIAID NIH HHS, Id: P30 AI027763
  • Agency: NIGMS NIH HHS, Id: P50 GM081879
  • Agency: NIGMS NIH HHS, Id: P50 GM082250
  • Agency: NEI NIH HHS, Id: PN2 EY016546
  • Agency: NEI NIH HHS, Id: PN2 EY016546
  • Agency: NIGMS NIH HHS, Id: R01 GM055040
  • Agency: NIGMS NIH HHS, Id: R01 GM056433
  • Agency: NIGMS NIH HHS, Id: R01 GM062583
  • Agency: NIGMS NIH HHS, Id: R01 GM084279
  • Agency: NIGMS NIH HHS, Id: R01 GM084448
  • Agency: NCRR NIH HHS, Id: RR01614
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

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