Systematic functional prioritization of protein posttranslational modifications.
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.
Cell
Date: Jul. 20, 2012
PubMed ID: 22817900
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- Interactions 1
- PTM Genes 6,805
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[Alphabetical]
[PTM Count]
Ubiquitination (28)
Ubiquitination (7)
Ubiquitination (2)
Adenine deaminase (adenine aminohydrolase); converts adenine to hypoxanthine; involved in purine salvage; transcriptionally regulated by nutrient levels and growth phase; Aah1p degraded upon entry into quiescence via SCF and the proteasome
Organism: Saccharomyces cerevisiae
Ubiquitination (6)
Ubiquitination (1)
Arginine/alanine amino peptidase; overproduction stimulates glycogen accumulation; AAP1 has a paralog, APE2, that arose from the whole genome duplication
Organism: Saccharomyces cerevisiae
Ubiquitination (15)
Ubiquitination (16)
Ubiquitination (3)
Ubiquitination (8)
Ubiquitination (5)
aminoadipate-semialdehyde dehydrogenase-phosphopantetheinyl transferase
Organism: Homo sapiens
Ubiquitination (6)
Ubiquitination (41)
Ubiquitination (3)
Ubiquitination (9)
Ubiquitination (2)
ATP-binding cassette, sub-family B (MDR/TAP), member 6 (Langereis blood group)
Organism: Homo sapiens
Ubiquitination (24)
Ubiquitination (1)
Ubiquitination (107)
Ubiquitination (73)
Ubiquitination (77)
Ubiquitination (219)
Ubiquitination (48)
Ubiquitination (102)
Ubiquitination (7)
Ubiquitination (4)
Ubiquitination (98)
Ubiquitination (23)
Ubiquitination (58)
Ubiquitination (24)
Ubiquitination (68)
Ubiquitination (94)
ATP-binding cassette, sub-family G (WHITE), member 2 (Junior blood group)
Organism: Homo sapiens
Ubiquitination (40)
Ubiquitination (25)
Ubiquitination (2)
Ubiquitination (5)
Ubiquitination (10)
Ubiquitination (5)
Ubiquitination (4)
Ubiquitination (2)
Ubiquitination (10)
Ubiquitination (14)
Ubiquitination (3)
Ubiquitination (4)
Ubiquitination (20)
Ubiquitination (1)
Actin-binding protein of the cortical actin cytoskeleton; important for activation of the Arp2/3 complex that plays a key role actin in cytoskeleton organization; inhibits barbed-end actin filament elongation; phosphorylation within its Proline-Rich Regio, mediated by Cdc28p and Pho85p, protects Abp1p from proteolysis mediated by its own PEST sequences; mammalian homologue of HIP-55 (hematopoietic progenitor kinase 1 [HPK1]-interacting protein of 55 kDa)
Organism: Saccharomyces cerevisiae
Ubiquitination (32)
Ubiquitination (1)
Ubiquitination (3)
Ubiquitination (3)
Ubiquitination (26)
Ubiquitination (2)
Ubiquitination (5)
Ubiquitination (10)
Ubiquitination (10)
Ubiquitination (5)
Ubiquitination (4)
Ubiquitination (7)
Acetyl-CoA carboxylase, biotin containing enzyme; catalyzes carboxylation of cytosolic acetyl-CoA to form malonyl-CoA and regulates histone acetylation by regulating the availablity of acetyl-CoA; required for de novo biosynthesis of long-chain fatty acids; ACC1 has a paralog, HFA1, that arose from the whole genome duplication
Organism: Saccharomyces cerevisiae
Ubiquitination (4)
Ubiquitination (12)
Ubiquitination (96)
Ubiquitination (3)
Protein that functions in the cell wall integrity pathway; functions upstream of Pkc1p; GFP-fusion protein expression is induced in response to the DNA-damaging agent MMS; non-tagged Ack1p is detected in purified mitochondria
Organism: Saccharomyces cerevisiae
Ubiquitination (8)
Ubiquitination (72)
Ubiquitination (4)
Ubiquitination (20)
Ubiquitination (8)
Ubiquitination (28)
Ubiquitination (19)
Ubiquitination (18)
Ubiquitination (6)
Ubiquitination (2)
Acetyl-coA synthetase isoform; along with Acs1p, acetyl-coA synthetase isoform is the nuclear source of acetyl-coA for histone acetylation; mutants affect global transcription; required for growth on glucose; expressed under anaerobic conditions
Organism: Saccharomyces cerevisiae
Ubiquitination (96)
Ubiquitination (60)
Ubiquitination (200)
Ubiquitination (8)
Ubiquitination (13)
Ubiquitination (4)
Actin; structural protein involved in cell polarization, endocytosis, and other cytoskeletal functions
Organism: Saccharomyces cerevisiae
Ubiquitination (13)
Ubiquitination (36)
Ubiquitination (16)
Ubiquitination (5)
Ubiquitination (13)
Ubiquitination (32)
Ubiquitination (21)
Ubiquitination (16)
Ubiquitination (42)
Ubiquitination (7)
Ubiquitination (4)
Ubiquitination (60)
Ubiquitination (5)
Ubiquitination (8)
Ubiquitination (36)
Ubiquitination (31)
Ubiquitination (20)
Ubiquitination (1)
Ubiquitination (5)
Ubiquitination (9)
Ubiquitination (12)
Ubiquitination (15)
Ubiquitination (9)
Ubiquitination (3)
Ubiquitination (40)
Ubiquitination (25)
Ubiquitination (1)
Ubiquitination (4)
Ubiquitination (5)
Ubiquitination (13)
Ubiquitination (5)
Ubiquitination (42)
Ubiquitination (4)
Ubiquitination (54)
Ubiquitination (12)
Ubiquitination (6)
Ubiquitination (25)
Ubiquitination (8)
Ubiquitination (7)
Ubiquitination (2)
N-succinyl-5-aminoimidazole-4-carboxamide ribotide synthetase; required for 'de novo' purine nucleotide biosynthesis; red pigment accumulates in mutant cells deprived of adenine; protein abundance increases in response to DNA replication stress
Organism: Saccharomyces cerevisiae
Ubiquitination (1)
Phosphoribosylaminoimidazole carboxylase; catalyzes a step in the 'de novo' purine nucleotide biosynthetic pathway; red pigment accumulates in mutant cells deprived of adenine
Organism: Saccharomyces cerevisiae
Ubiquitination (1)
Cytoplasmic trifunctional enzyme C1-tetrahydrofolate synthase; involved in single carbon metabolism and required for biosynthesis of purines, thymidylate, methionine, and histidine; null mutation causes auxotrophy for adenine and histidine
Organism: Saccharomyces cerevisiae
Ubiquitination (1)
Phosphoribosylpyrophosphate amidotransferase (PRPPAT); catalyzes first step of the 'de novo' purine nucleotide biosynthetic pathway; also known as amidophosphoribosyltransferase
Organism: Saccharomyces cerevisiae
Ubiquitination (8)
Enzyme of the 'de novo' purine nucleotide biosynthetic pathway; contains aminoimidazole ribotide synthetase and glycinamide ribotide synthetase activities
Organism: Saccharomyces cerevisiae
Ubiquitination (9)
Formylglycinamidine-ribonucleotide (FGAM)-synthetase; catalyzes a step in the 'de novo' purine nucleotide biosynthetic pathway
Organism: Saccharomyces cerevisiae
Ubiquitination (1)
Adenylosuccinate lyase; catalyzes two steps in the 'de novo' purine nucleotide biosynthetic pathway; expression is repressed by adenine and activated by Bas1p and Pho2p; mutations in human ortholog ADSL cause adenylosuccinase deficiency
Organism: Saccharomyces cerevisiae
Ubiquitination (4)
Enzyme of 'de novo' purine biosynthesis; contains both 5-aminoimidazole-4-carboxamide ribonucleotide transformylase and inosine monophosphate cyclohydrolase activities; ADE16 has a paralog, ADE17, that arose from the whole genome duplication; ade16 ade17 mutants require adenine and histidine
Organism: Saccharomyces cerevisiae
Ubiquitination (9)
Enzyme of 'de novo' purine biosynthesis; contains both 5-aminoimidazole-4-carboxamide ribonucleotide transformylase and inosine monophosphate cyclohydrolase activities; ADE17 has a paralog, ADE16, that arose from the whole genome duplication; ade16 ade17 mutants require adenine and histidine
Organism: Saccharomyces cerevisiae
Ubiquitination (14)
Alcohol dehydrogenase; fermentative isozyme active as homo- or heterotetramers; required for the reduction of acetaldehyde to ethanol, the last step in the glycolytic pathway; ADH1 has a paralog, ADH5, that arose from the whole genome duplication
Organism: Saccharomyces cerevisiae
Ubiquitination (7)
Glucose-repressible alcohol dehydrogenase II; catalyzes the conversion of ethanol to acetaldehyde; involved in the production of certain carboxylate esters; regulated by ADR1
Organism: Saccharomyces cerevisiae
Ubiquitination (1)
Alcohol dehydrogenase isoenzyme V; involved in ethanol production; ADH5 has a paralog, ADH1, that arose from the whole genome duplication
Organism: Saccharomyces cerevisiae
Ubiquitination (10)
Ubiquitination (2)
Ubiquitination (8)
Ubiquitination (8)
Ubiquitination (4)
Ubiquitination (3)
Adenylate kinase, required for purine metabolism; localized to the cytoplasm and the mitochondria; lacks cleavable signal sequence; protein abundance increases in response to DNA replication stress
Organism: Saccharomyces cerevisiae
Ubiquitination (36)
Ubiquitination (9)
Ubiquitination (2)
Ubiquitination (7)
Adenosine kinase; required for the utilization of S-adenosylmethionine (AdoMet); may be involved in recycling adenosine produced through the methyl cycle
Organism: Saccharomyces cerevisiae
Ubiquitination (5)
Ubiquitination (4)
Ubiquitination (8)
Ubiquitination (152)
Ubiquitination (17)
Ubiquitination (8)
Ubiquitination (5)
Ubiquitination (14)
Ubiquitination (16)
Ubiquitination (22)
Ubiquitination (21)
Ubiquitination (2)
Mitochondrial inner membrane m-AAA protease component; mediates degradation of misfolded or unassembled proteins and is also required for correct assembly of mitochondrial enzyme complexes; involved in cytoplasmic mRNA translation and aging
Organism: Saccharomyces cerevisiae
Ubiquitination (17)
Ubiquitination (21)
Ubiquitination (13)
Ubiquitination (16)
Ubiquitination (35)
Ubiquitination (24)
Ubiquitination (11)
Ubiquitination (3)
Low-affinity amino acid permease with broad substrate range; involved in uptake of asparagine, glutamine, and other amino acids; expression regulated by SPS plasma membrane amino acid sensor system (Ssy1p-Ptr3p-Ssy5p); AGP1 has a paralog, GNP1, that arose from the whole genome duplication
Organism: Saccharomyces cerevisiae
Ubiquitination (3)
Ubiquitination (12)
Ubiquitination (12)
Ubiquitination (28)
Ubiquitination (57)
Ubiquitination (19)
Ubiquitination (149)
Ubiquitination (12)
Ubiquitination (44)
Ubiquitination (2176)
Ubiquitination (6)
Thiol-specific peroxiredoxin; reduces hydroperoxides to protect against oxidative damage; function in vivo requires covalent conjugation to Urm1p
Organism: Saccharomyces cerevisiae
Ubiquitination (12)
Ubiquitination (9)
Ubiquitination (17)
Ubiquitination (6)
Ubiquitination (10)
Ubiquitination (4)
Ubiquitination (1)
Protein that regulates Cdc42p and Rho1p; functions in the late steps of cytokinesis and cell separation; sustains Rho1p at the cell division site after actomyosin ring contraction; inhibits the activation of Cdc42-Cla4 at the cell division site to prevent budding inside the old bud neck; transcription is regulated by Swi5p; null mutant displays elevated frequency of mitochondrial genome loss; relocalizes from bud neck to cytoplasm upon DNA replication stress
Organism: Saccharomyces cerevisiae
Ubiquitination (1)
aminoacyl tRNA synthetase complex-interacting multifunctional protein 1
Organism: Homo sapiens
Ubiquitination (2)
aminoacyl tRNA synthetase complex-interacting multifunctional protein 2
Organism: Homo sapiens
Ubiquitination (3)
Ubiquitination (1)
Actin cortical patch component; interacts with the actin depolymerizing factor cofilin; inhibits elongation of aged ADP-actin filaments decorated with cofilin to maintain a high level of assembly-competent actin species; required to restrict cofilin localization to cortical patches; putative regulator of cytokinesis; contains WD repeats; protein increases in abundance and relocalizes from cytoplasm to plasma membrane upon DNA replication stress
Organism: Saccharomyces cerevisiae
Ubiquitination (10)
Ubiquitination (22)
Ubiquitination (12)
Ubiquitination (12)
Ubiquitination (349)
Ubiquitination (2)
Ubiquitination (28)
Ubiquitination (25)
Ubiquitination (4)
Ubiquitination (6)
Ubiquitination (6)
Ubiquitination (9)
Ubiquitination (6)
Ubiquitination (3)
Ubiquitination (1)
Ankyrin repeat-containing protein; member of a family of putative palmitoyltransferases containing an Asp-His-His-Cys-cysteine rich (DHHC-CRD) domain; possibly involved in constitutive endocytosis of Ste3p; AKR2 has a paralog, AKR1, that arose from the whole genome duplication
Organism: Saccharomyces cerevisiae
Ubiquitination (4)
aldo-keto reductase family 7, member A2 (aflatoxin aldehyde reductase)
Organism: Homo sapiens
Ubiquitination (6)
aldo-keto reductase family 7, member A3 (aflatoxin aldehyde reductase)
Organism: Homo sapiens
Ubiquitination (40)
Ubiquitination (43)
Ubiquitination (7)
Ubiquitination (1)
Cytoplasmic and mitochondrial alanyl-tRNA synthetase; required for protein synthesis; point mutation (cdc64-1 allele) causes cell cycle arrest at G1; lethality of null mutation is functionally complemented by human homolog AARS; mutations in human homolog AARS are associated with autoimmune disease polymyositis/dermatomyositis
Organism: Saccharomyces cerevisiae
Ubiquitination (1)
Ubiquitination (2)
Shuttling pre-60S factor; involved in the biogenesis of ribosomal large subunit; interacts directly with Arx1p; responsible for Tif6p recycling defects in absence of Rei1p
Organism: Saccharomyces cerevisiae
Ubiquitination (8)
Ubiquitination (12)
Cytosolic aldehyde dehydrogenase; activated by Mg2+ and utilizes NADP+ as the preferred coenzyme; required for conversion of acetaldehyde to acetate; constitutively expressed; locates to the mitochondrial outer surface upon oxidative stress
Organism: Saccharomyces cerevisiae
Ubiquitination (3)
Ubiquitination (12)
Ubiquitination (44)
Ubiquitination (6)
Ubiquitination (6)
Ubiquitination (8)
Ubiquitination (40)
Ubiquitination (22)
Ubiquitination (2)
Ubiquitination (4)
Ubiquitination (13)
Ubiquitination (9)
Ubiquitination (20)
Ubiquitination (50)
Ubiquitination (126)
Ubiquitination (2)
Ubiquitination (21)
Ubiquitination (20)
Ubiquitination (6)
Ubiquitination (2)
Ubiquitination (9)
Ubiquitination (11)
Ubiquitination (20)
Ubiquitination (2)
Ubiquitination (4)
Ubiquitination (6)
Ubiquitination (3)
Ubiquitination (2)
Protein kinase; along with its paralog, ALK2, required for proper spindle positioning and nuclear segregation following mitotic arrest, proper organization of cell polarity factors in mitosis, proper localization of formins and polarity factors, and survival in cells that activate spindle assembly checkpoint; phosphorylated in response to DNA damage; ALK1 has a paralog, ALK2, that arose from the whole genome duplication; similar to mammalian haspins
Organism: Saccharomyces cerevisiae
Ubiquitination (3)
Ubiquitination (4)
Ubiquitination (1)
Ubiquitination (2)
Ubiquitination (14)
Ubiquitination (5)
Ubiquitination (3)
Ubiquitination (16)
Ubiquitination (3)
Alpha arrestin, substrate of calcineurin; controls nutrient-mediated intracellular sorting of permease Gap1p; interacts with AP-1 subunit Apl4p; dephosphorylation of Aly1p required for the endocytosis of Dip5p; may regulate endocytosis of plasma membrane proteins by recruiting ubiquitin ligase Rsp5p to plasma membrane targets; ALY1 has a paralog, ALY2, that arose from the whole genome duplication
Organism: Saccharomyces cerevisiae
Ubiquitination (4)
Alpha arrestin; controls nutrient-mediated intracellular sorting of permease Gap1p; interacts with AP-1 subunit Apl4p; phosphorylated by Npr1p and also by cyclin-CDK complex Pcl7p-Pho85p; promotes endocytosis of plasma membrane proteins; ALY2 has a paralog, ALY1, that arose from the whole genome duplication
Organism: Saccharomyces cerevisiae
Ubiquitination (1)
Ubiquitination (2)
Ubiquitination (33)
Ubiquitination (15)
Ubiquitination (2)
Ubiquitination (6)
Ubiquitination (8)
Ubiquitination (2)
Protein required for daughter cell separation; multiple mitotic checkpoints, and chromosome stability; contains 12 degenerate leucine-rich repeat motifs; expression is induced by the Mitotic Exit Network (MEN)
Organism: Saccharomyces cerevisiae
Ubiquitination (9)
Ubiquitination (6)
Ubiquitination (8)
Ubiquitination (175)
Ubiquitination (5)
Ubiquitination (12)
Ubiquitination (94)
Ubiquitination (119)
Ubiquitination (56)
Ubiquitination (8)
Ubiquitination (2)
Ubiquitination (70)
Ubiquitination (6)
Ubiquitination (4)
Ubiquitination (32)
Ubiquitination (15)
Ubiquitination (3)
Ubiquitination (5)
Ubiquitination (4)
Ubiquitination (6)
Ubiquitination (8)
Ubiquitination (76)
Ubiquitination (154)
Ubiquitination (19)
Ubiquitination (8)
Ubiquitination (5)
Ubiquitination (42)
Ubiquitination (3)
Ubiquitination (27)
Ubiquitination (34)
Ubiquitination (4)
Ubiquitination (1)
Ubiquitination (4)
Ubiquitination (12)
Ubiquitination (22)
Ubiquitination (42)
Ubiquitination (6)
Ubiquitination (40)
Ubiquitination (2)
Ubiquitination (2)
Ubiquitination (2)
Ubiquitination (54)
Ubiquitination (6)
Ubiquitination (30)
Ubiquitination (75)
Ubiquitination (162)
Ubiquitination (8)
Ubiquitination (8)
Ubiquitination (25)