ID   ICMT_HUMAN              Reviewed;         284 AA.
AC   O60725; Q6FHT0;
DT   20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1998, sequence version 1.
DT   27-MAR-2024, entry version 181.
DE   RecName: Full=Protein-S-isoprenylcysteine O-methyltransferase;
DE            EC=2.1.1.100 {ECO:0000269|PubMed:9614111};
DE   AltName: Full=Isoprenylcysteine carboxylmethyltransferase;
DE   AltName: Full=Prenylated protein carboxyl methyltransferase;
DE            Short=PPMT;
DE   AltName: Full=Prenylcysteine carboxyl methyltransferase;
DE            Short=pcCMT;
GN   Name=ICMT; Synonyms=PCCMT;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, ACTIVITY
RP   REGULATION, AND SUBCELLULAR LOCATION.
RC   TISSUE=Myeloid;
RX   PubMed=9614111; DOI=10.1074/jbc.273.24.15030;
RA   Dai Q., Choy E., Chiu V., Romano J., Slivka S.R., Steitz S.A.,
RA   Michaelis S., Philips M.R.;
RT   "Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic
RT   reticulum.";
RL   J. Biol. Chem. 273:15030-15034(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT   "Cloning of human full open reading frames in Gateway(TM) system entry
RT   vector (pDONR201).";
RL   Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [6]
RP   TISSUE SPECIFICITY.
RX   PubMed=10649571; DOI=10.1038/72101;
RA   Lin X., Antalffy B., Kang D., Orr H.T., Zoghbi H.Y.;
RT   "Polyglutamine expansion down-regulates specific neuronal genes before
RT   pathologic changes in SCA1.";
RL   Nat. Neurosci. 3:157-163(2000).
RN   [7]
RP   SUBCELLULAR LOCATION, AND MEMBRANE TOPOLOGY.
RX   PubMed=19158273; DOI=10.1128/mcb.01719-08;
RA   Wright L.P., Court H., Mor A., Ahearn I.M., Casey P.J., Philips M.R.;
RT   "Topology of mammalian isoprenylcysteine carboxyl methyltransferase
RT   determined in live cells with a fluorescent probe.";
RL   Mol. Cell. Biol. 29:1826-1833(2009).
CC   -!- FUNCTION: Catalyzes the post-translational methylation of isoprenylated
CC       C-terminal cysteine residues. {ECO:0000269|PubMed:9614111}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=[protein]-C-terminal S-[(2E,6E)-farnesyl]-L-cysteine + S-
CC         adenosyl-L-methionine = [protein]-C-terminal S-[(2E,6E)-farnesyl]-L-
CC         cysteine methyl ester + S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:21672, Rhea:RHEA-COMP:12125, Rhea:RHEA-COMP:12126,
CC         ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:90510,
CC         ChEBI:CHEBI:90511; EC=2.1.1.100;
CC         Evidence={ECO:0000269|PubMed:9614111};
CC   -!- ACTIVITY REGULATION: Competitively inhibited by N-acetyl-S-trans,trans-
CC       farnesyl-l-cysteine (AFC). {ECO:0000269|PubMed:9614111}.
CC   -!- INTERACTION:
CC       O60725; Q13520: AQP6; NbExp=3; IntAct=EBI-11721771, EBI-13059134;
CC       O60725; Q3SXY8: ARL13B; NbExp=3; IntAct=EBI-11721771, EBI-11343438;
CC       O60725; Q8N5M9: JAGN1; NbExp=3; IntAct=EBI-11721771, EBI-10266796;
CC       O60725; P48051: KCNJ6; NbExp=3; IntAct=EBI-11721771, EBI-12017638;
CC       O60725; P15941-11: MUC1; NbExp=3; IntAct=EBI-11721771, EBI-17263240;
CC       O60725; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-11721771, EBI-716063;
CC       O60725; Q6ZMZ0: RNF19B; NbExp=3; IntAct=EBI-11721771, EBI-2466594;
CC       O60725; Q13049: TRIM32; NbExp=3; IntAct=EBI-11721771, EBI-742790;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:19158273, ECO:0000269|PubMed:9614111}; Multi-pass
CC       membrane protein {ECO:0000269|PubMed:19158273}.
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed. Expressed at higher levels
CC       in the cerebellum and putamen than in other brain regions. Abundant
CC       expression seen in the Purkinje cells and pontine neurons.
CC       {ECO:0000269|PubMed:10649571}.
CC   -!- SIMILARITY: Belongs to the class VI-like SAM-binding methyltransferase
CC       superfamily. Isoprenylcysteine carboxyl methyltransferase family.
CC       {ECO:0000255|PROSITE-ProRule:PRU00897}.
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DR   EMBL; AF064084; AAC16554.1; -; mRNA.
DR   EMBL; CR541671; CAG46472.1; -; mRNA.
DR   EMBL; CR541711; CAG46512.1; -; mRNA.
DR   EMBL; AL031847; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471130; EAW71522.1; -; Genomic_DNA.
DR   EMBL; BC028168; AAH28168.1; -; mRNA.
DR   CCDS; CCDS61.1; -.
DR   RefSeq; NP_036537.1; NM_012405.3.
DR   AlphaFoldDB; O60725; -.
DR   SMR; O60725; -.
DR   BioGRID; 117026; 134.
DR   IntAct; O60725; 25.
DR   MINT; O60725; -.
DR   STRING; 9606.ENSP00000343552; -.
DR   BindingDB; O60725; -.
DR   ChEMBL; CHEMBL4699; -.
DR   iPTMnet; O60725; -.
DR   PhosphoSitePlus; O60725; -.
DR   SwissPalm; O60725; -.
DR   BioMuta; ICMT; -.
DR   EPD; O60725; -.
DR   jPOST; O60725; -.
DR   MassIVE; O60725; -.
DR   PaxDb; 9606-ENSP00000343552; -.
DR   PeptideAtlas; O60725; -.
DR   ProteomicsDB; 49571; -.
DR   Pumba; O60725; -.
DR   Antibodypedia; 27272; 213 antibodies from 26 providers.
DR   DNASU; 23463; -.
DR   Ensembl; ENST00000343813.10; ENSP00000343552.5; ENSG00000116237.16.
DR   GeneID; 23463; -.
DR   KEGG; hsa:23463; -.
DR   MANE-Select; ENST00000343813.10; ENSP00000343552.5; NM_012405.4; NP_036537.1.
DR   UCSC; uc001amk.4; human.
DR   AGR; HGNC:5350; -.
DR   CTD; 23463; -.
DR   DisGeNET; 23463; -.
DR   GeneCards; ICMT; -.
DR   HGNC; HGNC:5350; ICMT.
DR   HPA; ENSG00000116237; Low tissue specificity.
DR   MIM; 605851; gene.
DR   neXtProt; NX_O60725; -.
DR   OpenTargets; ENSG00000116237; -.
DR   PharmGKB; PA29598; -.
DR   VEuPathDB; HostDB:ENSG00000116237; -.
DR   eggNOG; KOG2628; Eukaryota.
DR   GeneTree; ENSGT00390000017394; -.
DR   HOGENOM; CLU_065200_0_1_1; -.
DR   InParanoid; O60725; -.
DR   OMA; YFGWFWR; -.
DR   OrthoDB; 5473160at2759; -.
DR   PhylomeDB; O60725; -.
DR   TreeFam; TF313769; -.
DR   BRENDA; 2.1.1.100; 2681.
DR   PathwayCommons; O60725; -.
DR   Reactome; R-HSA-163841; Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation.
DR   Reactome; R-HSA-9648002; RAS processing.
DR   SABIO-RK; O60725; -.
DR   SignaLink; O60725; -.
DR   BioGRID-ORCS; 23463; 80 hits in 1166 CRISPR screens.
DR   ChiTaRS; ICMT; human.
DR   GeneWiki; ICMT; -.
DR   GenomeRNAi; 23463; -.
DR   Pharos; O60725; Tchem.
DR   PRO; PR:O60725; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; O60725; Protein.
DR   Bgee; ENSG00000116237; Expressed in diaphragm and 213 other cell types or tissues.
DR   ExpressionAtlas; O60725; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0016020; C:membrane; TAS:ProtInc.
DR   GO; GO:0003880; F:protein C-terminal carboxyl O-methyltransferase activity; TAS:ProtInc.
DR   GO; GO:0004671; F:protein C-terminal S-isoprenylcysteine carboxyl O-methyltransferase activity; IDA:FlyBase.
DR   GO; GO:0006481; P:C-terminal protein methylation; TAS:ProtInc.
DR   GO; GO:0036211; P:protein modification process; TAS:ProtInc.
DR   GO; GO:0006612; P:protein targeting to membrane; TAS:ProtInc.
DR   GO; GO:0046498; P:S-adenosylhomocysteine metabolic process; IEA:Ensembl.
DR   GO; GO:0046499; P:S-adenosylmethioninamine metabolic process; IEA:Ensembl.
DR   Gene3D; 1.20.120.1630; -; 1.
DR   InterPro; IPR007269; ICMT_MeTrfase.
DR   InterPro; IPR025770; PPMT_MeTrfase.
DR   PANTHER; PTHR12714; PROTEIN-S ISOPRENYLCYSTEINE O-METHYLTRANSFERASE; 1.
DR   PANTHER; PTHR12714:SF9; PROTEIN-S-ISOPRENYLCYSTEINE O-METHYLTRANSFERASE; 1.
DR   Pfam; PF04140; ICMT; 1.
DR   PROSITE; PS51564; SAM_ICMT; 1.
DR   Genevisible; O60725; HS.
PE   1: Evidence at protein level;
KW   Endoplasmic reticulum; Membrane; Methyltransferase; Reference proteome;
KW   S-adenosyl-L-methionine; Transferase; Transmembrane; Transmembrane helix.
FT   CHAIN           1..284
FT                   /note="Protein-S-isoprenylcysteine O-methyltransferase"
FT                   /id="PRO_0000209894"
FT   TOPO_DOM        1..16
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        17..33
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        34..41
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        42..59
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        60..69
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        70..87
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        88..92
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        93..112
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        113..131
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        132..149
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        150..154
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        155..174
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        175..212
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        213..228
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        229
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        230..244
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        245..284
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   BINDING         190
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250|UniProtKB:D6WJ77"
FT   BINDING         197..200
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250|UniProtKB:D6WJ77"
FT   BINDING         205
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250|UniProtKB:D6WJ77"
FT   BINDING         210..213
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250|UniProtKB:D6WJ77"
FT   BINDING         247
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:D6WJ77"
FT   BINDING         251
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000250|UniProtKB:D6WJ77"
SQ   SEQUENCE   284 AA;  31938 MW;  C86741B13ACA611C CRC64;
     MAGCAARAPP GSEARLSLAT FLLGASVLAL PLLTRAGLQG RTGLALYVAG LNALLLLLYR
     PPRYQIAIRA CFLGFVFGCG TLLSFSQSSW SHFGWYMCSL SLFHYSEYLV TAVNNPKSLS
     LDSFLLNHSL EYTVAALSSW LEFTLENIFW PELKQITWLS VTGLLMVVFG ECLRKAAMFT
     AGSNFNHVVQ NEKSDTHTLV TSGVYAWFRH PSYVGWFYWS IGTQVMLCNP ICGVSYALTV
     WRFFRDRTEE EEISLIHFFG EEYLEYKKRV PTGLPFIKGV KVDL
//