Protein methylation (Homo sapiens)

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11369741215nucleoplasmcytosolmitochondrial matrixAdoMetN6AMT2VCPVCPKMTAdoMetMe3K79-EEF1A1AdoHcyMETTL10Me3K115-CALM1HSPA8AdoHcyMe3K200,Me3K203-ETFBAdoHcyCAMKMTMe2aR-RPS2Me3K561-HSPA8CALM1ETFBKMTMe3K135-KINMe3K315-VCPMe3K318-EEF1A1EEF2KMTAdoMetKINAdoMetAdoMetAdoHcyETFBMETTL22EEF1A1AdoHcyAdoMetEEF2PRMT3RPS2METTL21AAdoHcyMe3K525-EEF28, 108, 10


Methylation of lysine (Lys) and arginine (Arg) residues on non-histone proteins is a prevalent post-translational modification and important regulator of cellular signal transduction pathways including MAPK, WNT, BMP, Hippo and JAK–STAT. Crosstalk between methylation and other types of post-translational modifications and between histone and non-histone protein methylation is frequent, affecting cellular functions such as chromatin remodelling, gene transcription, protein synthesis, signal transduction and DNA repair (Biggar & Li 2015). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 8876725
Reactome version: 61
Reactome Author 
Reactome Author: Jupe, Steve

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  1. Tang J, Gary JD, Clarke S, Herschman HR.; ''PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation.''; PubMed
  2. Van Ness BG, Howard JB, Bodley JW.; ''ADP-ribosylation of elongation factor 2 by diphtheria toxin. NMR spectra and proposed structures of ribosyl-diphthamide and its hydrolysis products.''; PubMed
  3. Biggar KK, Li SS.; ''Non-histone protein methylation as a regulator of cellular signalling and function.''; PubMed
  4. Hamey JJ, Winter DL, Yagoub D, Overall CM, Hart-Smith G, Wilkins MR.; ''Novel N-terminal and Lysine Methyltransferases That Target Translation Elongation Factor 1A in Yeast and Human.''; PubMed
  5. Małecki J, Ho AY, Moen A, Dahl HA, Falnes PØ.; ''Human METTL20 is a mitochondrial lysine methyltransferase that targets the β subunit of electron transfer flavoprotein (ETFβ) and modulates its activity.''; PubMed
  6. Davydova E, Ho AY, Malecki J, Moen A, Enserink JM, Jakobsson ME, Loenarz C, Falnes PØ.; ''Identification and characterization of a novel evolutionarily conserved lysine-specific methyltransferase targeting eukaryotic translation elongation factor 2 (eEF2).''; PubMed
  7. Sun XJ, Wei J, Wu XY, Hu M, Wang L, Wang HH, Zhang QH, Chen SJ, Huang QH, Chen Z.; ''Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase.''; PubMed
  8. Van Ness BG, Howard JB, Bodley JW.; ''ADP-ribosylation of elongation factor 2 by diphtheria toxin. Isolation and properties of the novel ribosyl-amino acid and its hydrolysis products.''; PubMed
  9. Cloutier P, Lavallée-Adam M, Faubert D, Blanchette M, Coulombe B.; ''A newly uncovered group of distantly related lysine methyltransferases preferentially interact with molecular chaperones to regulate their activity.''; PubMed
  10. Shimazu T, Barjau J, Sohtome Y, Sodeoka M, Shinkai Y.; ''Selenium-based S-adenosylmethionine analog reveals the mammalian seven-beta-strand methyltransferase METTL10 to be an EF1A1 lysine methyltransferase.''; PubMed
  11. Magnani R, Dirk LM, Trievel RC, Houtz RL.; ''Calmodulin methyltransferase is an evolutionarily conserved enzyme that trimethylates Lys-115 in calmodulin.''; PubMed


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101602view11:47, 1 November 2018ReactomeTeamreactome version 66
101138view21:32, 31 October 2018ReactomeTeamreactome version 65
100666view20:05, 31 October 2018ReactomeTeamreactome version 64
100216view16:51, 31 October 2018ReactomeTeamreactome version 63
99767view15:16, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99326view12:47, 31 October 2018ReactomeTeamreactome version 62
93413view11:22, 9 August 2017ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
CALM1ProteinP62158 (Uniprot-TrEMBL)
CAMKMTProteinQ7Z624 (Uniprot-TrEMBL)
EEF1A1ProteinP68104 (Uniprot-TrEMBL)
EEF2KMTProteinQ96G04 (Uniprot-TrEMBL)
EEF2ProteinP13639 (Uniprot-TrEMBL)
ETFBKMTProteinQ8IXQ9 (Uniprot-TrEMBL)
ETFBProteinP38117 (Uniprot-TrEMBL)
HSPA8ProteinP11142 (Uniprot-TrEMBL)
KINProteinO60870 (Uniprot-TrEMBL)
METTL10ProteinQ5JPI9 (Uniprot-TrEMBL)
METTL21AProteinQ8WXB1 (Uniprot-TrEMBL)
METTL22ProteinQ9BUU2 (Uniprot-TrEMBL)
Me2aR-RPS2ProteinP15880 (Uniprot-TrEMBL)
Me3K115-CALM1ProteinP62158 (Uniprot-TrEMBL)
Me3K135-KINProteinO60870 (Uniprot-TrEMBL)
Me3K200,Me3K203-ETFBProteinP38117 (Uniprot-TrEMBL)
Me3K315-VCPProteinP55072 (Uniprot-TrEMBL)
Me3K318-EEF1A1ProteinP68104 (Uniprot-TrEMBL)
Me3K525-EEF2ProteinP13639 (Uniprot-TrEMBL)
Me3K561-HSPA8ProteinP11142 (Uniprot-TrEMBL)
Me3K79-EEF1A1ProteinP68104 (Uniprot-TrEMBL)
N6AMT2ProteinQ8WVE0 (Uniprot-TrEMBL)
PRMT3ProteinO60678 (Uniprot-TrEMBL)
RPS2ProteinP15880 (Uniprot-TrEMBL)
VCPKMTProteinQ9H867 (Uniprot-TrEMBL)
VCPProteinP55072 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AdoHcyArrowR-HSA-6786205 (Reactome)
AdoHcyArrowR-HSA-8879123 (Reactome)
AdoHcyArrowR-HSA-8931858 (Reactome)
AdoHcyArrowR-HSA-8931974 (Reactome)
AdoHcyArrowR-HSA-8932221 (Reactome)
AdoHcyArrowR-HSA-8932243 (Reactome)
AdoHcyArrowR-HSA-8932275 (Reactome)
AdoHcyArrowR-HSA-8932276 (Reactome)
AdoHcyArrowR-HSA-8932413 (Reactome)
AdoMetR-HSA-6786205 (Reactome)
AdoMetR-HSA-8879123 (Reactome)
AdoMetR-HSA-8931858 (Reactome)
AdoMetR-HSA-8931974 (Reactome)
AdoMetR-HSA-8932221 (Reactome)
AdoMetR-HSA-8932243 (Reactome)
AdoMetR-HSA-8932275 (Reactome)
AdoMetR-HSA-8932276 (Reactome)
AdoMetR-HSA-8932413 (Reactome)
CALM1R-HSA-6786205 (Reactome)
CAMKMTmim-catalysisR-HSA-6786205 (Reactome)
EEF1A1R-HSA-8931974 (Reactome)
EEF1A1R-HSA-8932413 (Reactome)
EEF2KMTmim-catalysisR-HSA-8932243 (Reactome)
EEF2R-HSA-8932243 (Reactome)
ETFBKMTmim-catalysisR-HSA-8931858 (Reactome)
ETFBR-HSA-8931858 (Reactome)
HSPA8R-HSA-8932221 (Reactome)
KINR-HSA-8932275 (Reactome)
METTL10mim-catalysisR-HSA-8932413 (Reactome)
METTL21Amim-catalysisR-HSA-8932221 (Reactome)
METTL22mim-catalysisR-HSA-8932275 (Reactome)
Me2aR-RPS2ArrowR-HSA-8879123 (Reactome)
Me3K115-CALM1ArrowR-HSA-6786205 (Reactome)
Me3K135-KINArrowR-HSA-8932275 (Reactome)
Me3K200,Me3K203-ETFBArrowR-HSA-8931858 (Reactome)
Me3K315-VCPArrowR-HSA-8932276 (Reactome)
Me3K318-EEF1A1ArrowR-HSA-8932413 (Reactome)
Me3K525-EEF2ArrowR-HSA-8932243 (Reactome)
Me3K561-HSPA8ArrowR-HSA-8932221 (Reactome)
Me3K79-EEF1A1ArrowR-HSA-8931974 (Reactome)
N6AMT2mim-catalysisR-HSA-8931974 (Reactome)
PRMT3mim-catalysisR-HSA-8879123 (Reactome)
R-HSA-6786205 (Reactome) Calmodulin (CALM1) is a ubiquitous key mediator of Ca2+-dependent signalling and is subject to regulatory post-translational modifications which can affect protein-protein interactions. CALM1 is frequently trimethylated at Lys-115 which can influence changes in growth and development and its activator properties with target enzymes. The cytosolic enzyme calmodulin-lysine N-methyltransferase (CAMKMT) catalyses the transfer of 3 methyl groups from high energy donors S-adenosyl-L-methionine (AdoMet) to lysine residue 115 in CALM1, forming a trimethylated protein (triMe-K115-CALM1) (Magnani et al. 2010).
R-HSA-8879123 (Reactome) Protein arginine methyltransferase 3 (PRMT3) is a cytosolic enzyme that catalyzes the formation of omega-mono- or asymmetric dimethylarginine (Tang et al. 1998). It has a unique substrate binding N-terminal C2H2 Zn finger domain and a catalytic C-terminal domain that is homologous to other PRMTs (Zhang et al. 2000). PRMT3 associates with ribosomes in the cytosol, which contain its main in vivo substrate, the small ribosomal subunit Ribosomal protein S2 (RPS2). PRMT3 methylates arginines in the RG-rich N-terminal tail of RPS2 forming asymmetric dimethylarginines (Swiercz et al. 2005). Prmt3–null mice show developmental delay during embryogenesis and have embryos that are markedly smaller than wt , though size at birth is normal suggesting that PRMT3 loss can be compensated for in most cell types but may not be in under conditions that demand extremely fast protein synthesis (Swiercz et al. 2007).
R-HSA-8931858 (Reactome) Electron transfer flavoprotein beta subunit lysine methyltransferase (ETFBKMT, METTL20) specifically methylates Lys-200 and Lys-203 of Electron transfer flavoprotein beta (ETFB) ) (Rhein et al 2014, Malecki et al. 2015). ETF shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase (Ramsay et al. 1987). ETFB is proposed to contain 'recognition loop' at residues 191–200, responsible for interaction with the dehydrogenases (Toogood et al. 2004). Methylation of ETF impairs its ability to extract electrons from two acyl-CoA dehydrogenases, MCAD and GCDH, suggesting a functional role for ETFBKMT-mediated methylation of ETFB (Malecki et al. 2015).
R-HSA-8931974 (Reactome) Eukaryotic elongation factor 1A (EEF1A) is an essential, highly methylated protein that facilitates translational elongation by delivering aminoacyl-tRNAs to ribosomes. EEF1AKMT1 (N6AMT2) trimethylates EEF1A at Lys-79, a high-stoichiometry N-terminal site that is conserved from yeast to humans (Hamey et al. 2016).
R-HSA-8932221 (Reactome) Protein N-lysine methyltransferase METTL21A trimethylates lysine-561 of Heat shock cognate 71 kDa protein (HSPA8) and corresponding lysine residues in other Hsp70 isoforms (Jakobsson et al. 2013, Cloutier et al. 2013).
R-HSA-8932243 (Reactome) Protein-lysine N-methyltransferase EEF2KMT (EEF2KMT) catalyzes the trimethylation of eukaryotic elongation factor 2 (EEF2) on Lys-525.
R-HSA-8932275 (Reactome) METTL22 trimethylates lysine-135 of DNA/RNA-binding protein KIN17 (KIN) (Cloutier et al. 2013)
R-HSA-8932276 (Reactome) Protein N-lysine methyltransferase METTL21D (VCPKMT) trimethylates lysine-315 of VCP (Kernstock et al. 2012, Cloutier et al. 2013).
R-HSA-8932413 (Reactome) Protein-lysine N-methyltransferase METTL10 trimethylates Elongation factor 1-alpha 1 (EF1A1) at lysine-318 (Shimazu et al. 2014).
RPS2R-HSA-8879123 (Reactome)
VCPKMTmim-catalysisR-HSA-8932276 (Reactome)
VCPR-HSA-8932276 (Reactome)
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