ICMT (protein-S-isoprenylcysteine O-methyltransferase; EC 2.1.1.100) is a polytopic, multi-pass integral membrane enzyme of the endoplasmic reticulum that carries out the third and final step of CAAX-box protein processing. After a CAAX-motif protein has been prenylated (by farnesyltransferase or geranylgeranyltransferase-I) and its terminal -AAX tripeptide removed proteolytically (by RCE1), ICMT uses S-adenosyl-L-methionine to carboxymethylate (methyl-esterify) the newly exposed alpha-carboxyl group of the C-terminal prenylcysteine, yielding the prenylcysteine methyl ester and S-adenosyl-L-homocysteine. This methylation neutralizes the negative charge of the prenylcysteine and increases the hydrophobicity and membrane affinity of the modified protein. Substrates include RAS and related small GTPases (e.g. Cdc42, RhoA) and certain RAB GTPases (RAB7, RAB8), as well as the gamma subunits of heterotrimeric G proteins. ICMT is a SAM-dependent methyltransferase of the class VI-like SAM-binding superfamily and requires divalent cations for activity. Because carboxymethylation is required for proper membrane localization and signaling of RAS proteins, ICMT is an anticancer drug target.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004671 protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred (PAN-GO) molecular function. This is the correct and well-supported core catalytic activity of ICMT, consistent with the UniProt EC 2.1.1.100 assignment and with experimental (IDA/TAS) annotations for the same term. Supporting Evidence: file:human/ICMT/ICMT-uniprot.txt Catalyzes the post-translational methylation of isoprenylated |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred ER localization (is_active_in). Correct: ICMT is an ER-resident enzyme. The more specific location is the ER membrane (GO:0005789); this parent-level term is accurate and consistent with experimental data. Supporting Evidence: PMID:19158273 integral membrane protein restricted to the endoplasmic reticulum |
| GO:0004671 protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the core methyltransferase activity via combined IEA methods (ARBA, InterPro, RHEA:21672, EC 2.1.1.100). Redundant with the experimental IDA/TAS annotations but correct. Supporting Evidence: file:human/ICMT/ICMT-uniprot.txt Catalyzes the post-translational methylation of isoprenylated |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic ER localization. Correct but less specific than the experimentally supported ER membrane term (GO:0005789). Supporting Evidence: PMID:19158273 integral membrane protein restricted to the endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to ER membrane. This is the correct, specific core localization of ICMT, consistent with the experimental IDA/EXP annotations and the UniProt SUBCELLULAR LOCATION statement. Supporting Evidence: file:human/ICMT/ICMT-uniprot.txt Endoplasmic reticulum membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic "membrane" from InterPro. ICMT is indeed a multi-pass membrane protein, but this term is far less informative than the specific ER membrane localization (GO:0005789) that is experimentally supported. Supporting Evidence: file:human/ICMT/ICMT-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from the HuRI high-throughput yeast two-hybrid interactome (Luck et al. 2020). The reported partners (e.g. MUC1, KCNJ6, TRIM32, JAGN1, AQP6, ARL13B, PDZK1IP1, RNF19B) have no established functional relationship to ICMT's methyltransferase activity and this term conveys no specific functional information. Retained (experimental IPI) but flagged as uninformative/over-annotated. |
| GO:0071469 cellular response to alkaline pH | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from the rat ortholog (Q9WVM4) via Ensembl Compara. There is no direct human evidence linking ICMT to alkaline pH responses, and this single ortholog-based electronic inference is not part of ICMT's core biology (CAAX-processing carboxymethylation). Weakly supported and not core. |
| GO:0004671 protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity | IDA PMID:10441503 The carboxyl methyltransferase modifying G proteins is a met... | ACCEPT | Summary: Direct assay of prenylated protein carboxyl methyltransferase (PPMT/ICMT) activity. The paper characterizes the enzyme as a metalloenzyme that methylates isoprenylated C-terminal cysteines of small G proteins (Ras, Cdc42, RhoA, Rab1) and heterotrimeric G-protein gamma subunits, directly supporting the core molecular function. Supporting Evidence: PMID:10441503 posttranslational methylation of isoprenylated C-terminal cysteine residues |
| GO:0004671 protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity | TAS PMID:9614111 Mammalian prenylcysteine carboxyl methyltransferase is in th... | ACCEPT | Summary: Author statement from the original molecular characterization of the first mammalian pcCMT/ICMT, the third of three CAAX-processing enzymes. Supports the core methyltransferase activity; UniProt draws the EC 2.1.1.100 catalytic-activity assignment from this work. Supporting Evidence: PMID:9614111 posttranslationally modify C-terminal CAAX motifs and thereby target CAAX |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:9614111 Mammalian prenylcysteine carboxyl methyltransferase is in th... | ACCEPT | Summary: Experimental localization: mammalian pcCMT/ICMT is restricted to the endoplasmic reticulum, not the plasma membrane. Directly supports the core ER membrane location. Supporting Evidence: PMID:9614111 Mammalian pcCMT was not expressed at the plasma membrane |
| GO:0004671 protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity | IDA PMID:29051265 Regulation of NOTCH signaling by RAB7 and RAB8 requires carb... | ACCEPT | Summary: Direct evidence that ICMT methylesterifies C-terminal prenylcysteine residues of CaaX proteins and RAB GTPases (RAB7, RAB8). Supports the core carboxymethyltransferase activity and extends the substrate range to specific RABs. Supporting Evidence: PMID:29051265 Isoprenylcysteine carboxyl methyltransferase (ICMT) methylesterifies C-terminal |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:19158273 Topology of mammalian isoprenylcysteine carboxyl methyltrans... | ACCEPT | Summary: Live-cell topology mapping confirms ICMT is an integral ER membrane protein that traverses the ER membrane eight times, with N and C termini in the cytosol. Directly supports the core ER membrane localization. Supporting Evidence: PMID:19158273 integral membrane protein restricted to the endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-6788650 | ACCEPT | Summary: Reactome reaction (ICMT:Zn2+ transfers CH3 from AdoMet to isoprenylated proteins) places the enzyme in the ER membrane. Consistent with experimental localization. Supporting Evidence: file:human/ICMT/ICMT-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9647977 | ACCEPT | Summary: Reactome reaction (ICMT methylates S-Farn RAS proteins) places ICMT in the ER membrane. Consistent with the core localization. Supporting Evidence: file:human/ICMT/ICMT-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9656775 | ACCEPT | Summary: Reactome reaction (Cysmethynil binds ICMT:Zn2+) modeling inhibitor binding to the ER-membrane enzyme. Localization consistent with experimental data. Supporting Evidence: file:human/ICMT/ICMT-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | IDA PMID:9614111 Mammalian prenylcysteine carboxyl methyltransferase is in th... | KEEP AS NON CORE | Summary: Experimental ER localization (MGI). Correct; the more specific location is the ER membrane (GO:0005789), which is separately and experimentally annotated. Supporting Evidence: PMID:9614111 Mammalian pcCMT was not expressed at the plasma membrane |
| GO:0006612 protein targeting to membrane | TAS PMID:9614111 Mammalian prenylcysteine carboxyl methyltransferase is in th... | KEEP AS NON CORE | Summary: ICMT carboxymethylation is the final CAAX-processing step that increases membrane affinity and helps target CAAX proteins (e.g. RAS) to the plasma membrane. This term captures a downstream biological consequence of ICMT's activity on its substrates rather than ICMT's own molecular function, so it is kept as a non-core process annotation. The core process is the methylation reaction itself (C-terminal protein methylation, GO:0006481). Supporting Evidence: PMID:9614111 posttranslationally modify C-terminal CAAX motifs and thereby target CAAX |
| GO:0006481 C-terminal protein methylation | IDA PMID:29051265 Regulation of NOTCH signaling by RAB7 and RAB8 requires carb... | NEW | Summary: Proposed core biological process capturing ICMT's own reaction - methylation of the C-terminal (prenyl)cysteine residue of its substrates. This is the process directly effected by ICMT's molecular function (GO:0004671) and is more informative than the downstream "protein targeting to membrane" consequence currently in GOA. Not present in the current GOA set for human ICMT. Supporting Evidence: PMID:29051265 Isoprenylcysteine carboxyl methyltransferase (ICMT) methylesterifies C-terminal |
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