title: Systematic functional prioritization of protein posttranslational modifications.
abstract: 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.
authors: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94107, USA. pedro.beltrao@ucsf.edu
authors: Pedro
authors: P
authors: Beltrao
authors: Véronique
authors: V
authors: Albanèse
authors: Lillian R
authors: LR
authors: Kenner
authors: Danielle L
authors: DL
authors: Swaney
authors: Alma
authors: A
authors: Burlingame
authors: Judit
authors: J
authors: Villén
authors: Wendell A
authors: WA
authors: Lim
authors: James S
authors: JS
authors: Fraser
authors: Judith
authors: J
authors: Frydman
authors: Nevan J
authors: NJ
authors: Krogan
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D056890:Eukaryota / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D016415:Sequence Alignment; D054875:Ubiquitination
chemical_list: D018840:HSP70 Heat-Shock Proteins