CBPM_HUMAN
ID CBPM_HUMAN Reviewed; 443 AA.
AC P14384; B2R800; Q9H2K9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 11-JUL-2001, sequence version 2.
DT 03-AUG-2022, entry version 209.
DE RecName: Full=Carboxypeptidase M;
DE Short=CPM;
DE EC=3.4.17.12 {ECO:0000269|PubMed:12457462};
DE Flags: Precursor;
GN Name=CPM;
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], AND PROTEIN SEQUENCE OF 18-48.
RC TISSUE=Placenta;
RX PubMed=2753907; DOI=10.1016/s0021-9258(18)51610-0;
RA Tan F., Chan S.J., Steiner D.F., Schilling J.W., Skidgel R.A.;
RT "Molecular cloning and sequencing of the cDNA for human membrane-bound
RT carboxypeptidase M. Comparison with carboxypeptidases A, B, H, and N.";
RL J. Biol. Chem. 264:13165-13170(1989).
RN [2]
RP SEQUENCE REVISION.
RA Skidgel R.A.;
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11147789; DOI=10.2337/diabetes.50.1.204;
RA Bektas A., Hughes J.N., Warram J.H., Krolewski A.S., Doria A.;
RT "Type 2 diabetes locus on 12q15: further mapping and mutation screening of
RT two candidate genes.";
RL Diabetes 50:204-208(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11934264; DOI=10.1515/bc.2002.028;
RA Pessoa L.G., Guerreiro da S.I., Baptista H.A., Pesquero J.L., Paiva A.C.M.,
RA Bader M., Pesquero J.B.;
RT "Molecular structure and alternative splicing of the human carboxypeptidase
RT M gene.";
RL Biol. Chem. 383:263-269(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [7]
RP PROTEIN SEQUENCE OF 18-21, GPI-ANCHOR AT SER-423, BIOPHYSICOCHEMICAL
RP PROPERTIES, FUNCTION, CATALYTIC ACTIVITY, SITE, SUBCELLULAR LOCATION,
RP IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS OF GLU-277; GLU-281
RP AND SER-423.
RX PubMed=12457462; DOI=10.1042/bj20021495;
RA Tan F., Balsitis S., Black J.K., Bloechl A., Mao J.-F., Becker R.P.,
RA Schacht D., Skidgel R.A.;
RT "Effect of mutation of two critical glutamic acid residues on the activity
RT and stability of human carboxypeptidase M and characterization of its
RT signal for glycosylphosphatidylinositol anchoring.";
RL Biochem. J. 370:567-578(2003).
RN [8]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-115 AND ASN-164.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 18-443 IN COMPLEX WITH ZINC IONS,
RP DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-38 AND ASN-115.
RX PubMed=15066430; DOI=10.1016/j.jmb.2004.02.058;
RA Reverter D., Maskos K., Tan F., Skidgel R.A., Bode W.;
RT "Crystal structure of human carboxypeptidase M, a membrane-bound enzyme
RT that regulates peptide hormone activity.";
RL J. Mol. Biol. 338:257-269(2004).
CC -!- FUNCTION: Specifically removes C-terminal basic residues (Arg or Lys)
CC from peptides and proteins. It is believed to play important roles in
CC the control of peptide hormone and growth factor activity at the cell
CC surface, and in the membrane-localized degradation of extracellular
CC proteins. {ECO:0000269|PubMed:12457462}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Cleavage of C-terminal arginine or lysine residues from
CC polypeptides.; EC=3.4.17.12; Evidence={ECO:0000269|PubMed:12457462};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:15066430};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:15066430};
CC -!- ACTIVITY REGULATION: Inhibited by O-phenanthroline and MGTA and
CC activated by cobalt.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=59 uM for synthetic dansyl-Ala-Arg {ECO:0000269|PubMed:12457462};
CC KM=57 uM for placental peptide hormones
CC {ECO:0000269|PubMed:12457462};
CC pH dependence:
CC Optimum pH is 7.0. {ECO:0000269|PubMed:12457462};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12457462};
CC Lipid-anchor, GPI-anchor {ECO:0000269|PubMed:12457462}.
CC -!- SIMILARITY: Belongs to the peptidase M14 family. {ECO:0000305}.
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DR EMBL; J04970; AAA35651.2; -; mRNA.
DR EMBL; AF262947; AAG47641.1; -; Genomic_DNA.
DR EMBL; AF262940; AAG47641.1; JOINED; Genomic_DNA.
DR EMBL; AF262941; AAG47641.1; JOINED; Genomic_DNA.
DR EMBL; AF262942; AAG47641.1; JOINED; Genomic_DNA.
DR EMBL; AF262943; AAG47641.1; JOINED; Genomic_DNA.
DR EMBL; AF262944; AAG47641.1; JOINED; Genomic_DNA.
DR EMBL; AF262945; AAG47641.1; JOINED; Genomic_DNA.
DR EMBL; AF262946; AAG47641.1; JOINED; Genomic_DNA.
DR EMBL; AF368463; AAK69717.1; -; mRNA.
DR EMBL; AK313180; BAG35997.1; -; mRNA.
DR EMBL; BC022276; AAH22276.1; -; mRNA.
DR CCDS; CCDS8987.1; -.
DR PIR; A32619; A32619.
DR RefSeq; NP_001005502.1; NM_001005502.2.
DR RefSeq; NP_001865.1; NM_001874.4.
DR RefSeq; NP_938079.1; NM_198320.3.
DR PDB; 1UWY; X-ray; 3.00 A; A=18-443.
DR PDBsum; 1UWY; -.
DR AlphaFoldDB; P14384; -.
DR SMR; P14384; -.
DR BioGRID; 107760; 57.
DR IntAct; P14384; 37.
DR STRING; 9606.ENSP00000448517; -.
DR BindingDB; P14384; -.
DR ChEMBL; CHEMBL3038; -.
DR GuidetoPHARMACOLOGY; 1596; -.
DR MEROPS; M14.006; -.
DR GlyGen; P14384; 7 sites.
DR iPTMnet; P14384; -.
DR PhosphoSitePlus; P14384; -.
DR BioMuta; CPM; -.
DR DMDM; 14916957; -.
DR EPD; P14384; -.
DR jPOST; P14384; -.
DR MassIVE; P14384; -.
DR MaxQB; P14384; -.
DR PaxDb; P14384; -.
DR PeptideAtlas; P14384; -.
DR PRIDE; P14384; -.
DR ProteomicsDB; 53049; -.
DR Antibodypedia; 975; 358 antibodies from 35 providers.
DR DNASU; 1368; -.
DR Ensembl; ENST00000338356.7; ENSP00000339157.3; ENSG00000135678.12.
DR Ensembl; ENST00000546373.5; ENSP00000447255.1; ENSG00000135678.12.
DR Ensembl; ENST00000551568.6; ENSP00000448517.1; ENSG00000135678.12.
DR GeneID; 1368; -.
DR KEGG; hsa:1368; -.
DR MANE-Select; ENST00000551568.6; ENSP00000448517.1; NM_198320.5; NP_938079.1.
DR UCSC; uc001sup.4; human.
DR CTD; 1368; -.
DR DisGeNET; 1368; -.
DR GeneCards; CPM; -.
DR HGNC; HGNC:2311; CPM.
DR HPA; ENSG00000135678; Tissue enhanced (adipose).
DR MIM; 114860; gene.
DR neXtProt; NX_P14384; -.
DR OpenTargets; ENSG00000135678; -.
DR PharmGKB; PA26828; -.
DR VEuPathDB; HostDB:ENSG00000135678; -.
DR eggNOG; KOG2649; Eukaryota.
DR GeneTree; ENSGT00940000158580; -.
DR HOGENOM; CLU_006722_1_0_1; -.
DR InParanoid; P14384; -.
DR OMA; HLTKVVI; -.
DR OrthoDB; 101221at2759; -.
DR PhylomeDB; P14384; -.
DR TreeFam; TF315592; -.
DR BRENDA; 3.4.17.12; 2681.
DR PathwayCommons; P14384; -.
DR Reactome; R-HSA-163125; Post-translational modification: synthesis of GPI-anchored proteins.
DR SABIO-RK; P14384; -.
DR SignaLink; P14384; -.
DR SIGNOR; P14384; -.
DR BioGRID-ORCS; 1368; 16 hits in 1078 CRISPR screens.
DR ChiTaRS; CPM; human.
DR EvolutionaryTrace; P14384; -.
DR GeneWiki; CPM_(gene); -.
DR GenomeRNAi; 1368; -.
DR Pharos; P14384; Tchem.
DR PRO; PR:P14384; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; P14384; protein.
DR Bgee; ENSG00000135678; Expressed in lower lobe of lung and 182 other tissues.
DR ExpressionAtlas; P14384; baseline and differential.
DR Genevisible; P14384; HS.
DR GO; GO:0031225; C:anchored component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0009986; C:cell surface; HDA:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004180; F:carboxypeptidase activity; TAS:ProtInc.
DR GO; GO:0004181; F:metallocarboxypeptidase activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0006518; P:peptide metabolic process; IBA:GO_Central.
DR GO; GO:0016485; P:protein processing; IBA:GO_Central.
DR CDD; cd03866; M14_CPM; 1.
DR InterPro; IPR008969; CarboxyPept-like_regulatory.
DR InterPro; IPR033842; CPM_N.
DR InterPro; IPR000834; Peptidase_M14.
DR Pfam; PF00246; Peptidase_M14; 1.
DR PRINTS; PR00765; CRBOXYPTASEA.
DR SMART; SM00631; Zn_pept; 1.
DR SUPFAM; SSF49464; SSF49464; 1.
DR PROSITE; PS00132; CARBOXYPEPT_ZN_1; 1.
DR PROSITE; PS00133; CARBOXYPEPT_ZN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Carboxypeptidase; Cell membrane; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; GPI-anchor; Hydrolase; Lipoprotein; Membrane;
KW Metal-binding; Metalloprotease; Protease; Reference proteome; Signal; Zinc.
FT SIGNAL 1..17
FT /evidence="ECO:0000269|PubMed:12457462,
FT ECO:0000269|PubMed:2753907"
FT CHAIN 18..423
FT /note="Carboxypeptidase M"
FT /id="PRO_0000004391"
FT PROPEP 424..443
FT /note="Removed in mature form"
FT /evidence="ECO:0000305"
FT /id="PRO_0000251910"
FT ACT_SITE 281
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000305|PubMed:12457462"
FT BINDING 83
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:15066430,
FT ECO:0007744|PDB:1UWY"
FT BINDING 86
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:15066430,
FT ECO:0007744|PDB:1UWY"
FT BINDING 190
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:15066430,
FT ECO:0007744|PDB:1UWY"
FT SITE 277
FT /note="Probable structural role"
FT /evidence="ECO:0000305|PubMed:12457462"
FT LIPID 423
FT /note="GPI-anchor amidated serine"
FT /evidence="ECO:0000269|PubMed:12457462"
FT CARBOHYD 38
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15066430"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15066430,
FT ECO:0000269|PubMed:19159218, ECO:0007744|PDB:1UWY"
FT CARBOHYD 164
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT CARBOHYD 363
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 384
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 138..285
FT /evidence="ECO:0000269|PubMed:15066430,
FT ECO:0007744|PDB:1UWY"
FT DISULFID 242..284
FT /evidence="ECO:0000269|PubMed:15066430,
FT ECO:0007744|PDB:1UWY"
FT DISULFID 341..410
FT /evidence="ECO:0000269|PubMed:15066430,
FT ECO:0007744|PDB:1UWY"
FT VARIANT 24
FT /note="R -> H (in dbSNP:rs7978197)"
FT /id="VAR_048600"
FT VARIANT 133
FT /note="V -> I (in dbSNP:rs7309831)"
FT /id="VAR_048601"
FT MUTAGEN 277
FT /note="E->A: 5-fold decrease in substrate affinity. 22-fold
FT decrease in specific affinity. 104-fold decrease in
FT catalytic efficiency. Greatly reduced heat stability."
FT /evidence="ECO:0000269|PubMed:12457462"
FT MUTAGEN 277
FT /note="E->Q: 2-fold decrease in substrate affinity. Small
FT increase in specific affinity. Reduced heat stability by
FT 50%."
FT /evidence="ECO:0000269|PubMed:12457462"
FT MUTAGEN 281
FT /note="E->Q: Abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:12457462"
FT MUTAGEN 423
FT /note="S->A,T: Expressed on cell membrane. Released from
FT membrane by PI-PLC."
FT /evidence="ECO:0000269|PubMed:12457462"
FT MUTAGEN 423
FT /note="S->P: Little expression on cell membrane.
FT Perinuclear localization. Not released from membrane by PI-
FT PLC."
FT /evidence="ECO:0000269|PubMed:12457462"
FT HELIX 25..38
FT /evidence="ECO:0007829|PDB:1UWY"
FT TURN 39..41
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 42..50
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 56..65
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 75..80
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 88..103
FT /evidence="ECO:0007829|PDB:1UWY"
FT TURN 104..106
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 108..116
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 118..123
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 127..132
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 159..161
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 169..180
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 183..185
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 188..190
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 192..199
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 205..207
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 209..211
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 219..231
FT /evidence="ECO:0007829|PDB:1UWY"
FT TURN 234..238
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 243..245
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 252..255
FT /evidence="ECO:0007829|PDB:1UWY"
FT TURN 256..258
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 265..271
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 279..287
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 290..292
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 293..298
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 301..308
FT /evidence="ECO:0007829|PDB:1UWY"
FT HELIX 309..312
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 314..320
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 331..334
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 350..353
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 357..365
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 367..369
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 372..378
FT /evidence="ECO:0007829|PDB:1UWY"
FT STRAND 383..386
FT /evidence="ECO:0007829|PDB:1UWY"
FT TURN 415..418
FT /evidence="ECO:0007829|PDB:1UWY"
SQ SEQUENCE 443 AA; 50514 MW; 98EB0C94E201B901 CRC64;
MDFPCLWLGL LLPLVAALDF NYHRQEGMEA FLKTVAQNYS SVTHLHSIGK SVKGRNLWVL
VVGRFPKEHR IGIPEFKYVA NMHGDETVGR ELLLHLIDYL VTSDGKDPEI TNLINSTRIH
IMPSMNPDGF EAVKKPDCYY SIGRENYNQY DLNRNFPDAF EYNNVSRQPE TVAVMKWLKT
ETFVLSANLH GGALVASYPF DNGVQATGAL YSRSLTPDDD VFQYLAHTYA SRNPNMKKGD
ECKNKMNFPN GVTNGYSWYP LQGGMQDYNY IWAQCFEITL ELSCCKYPRE EKLPSFWNNN
KASLIEYIKQ VHLGVKGQVF DQNGNPLPNV IVEVQDRKHI CPYRTNKYGE YYLLLLPGSY
IINVTVPGHD PHITKVIIPE KSQNFSALKK DILLPFQGQL DSIPVSNPSC PMIPLYRNLP
DHSAATKPSL FLFLVSLLHI FFK
