ID CBPZ_HUMAN Reviewed; 652 AA. AC Q66K79; O00520; Q96MX2; DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 2. DT 24-JAN-2024, entry version 150. DE RecName: Full=Carboxypeptidase Z; DE Short=CPZ; DE EC=3.4.17.-; DE Flags: Precursor; GN Name=CPZ; 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] (ISOFORM 2), FUNCTION, ENZYME ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, TISSUE SPECIFICITY, AND RP VARIANTS PRO-5; LEU-6 AND THR-486. RX PubMed=9099699; DOI=10.1074/jbc.272.16.10543; RA Song L., Fricker L.D.; RT "Cloning and expression of human carboxypeptidase Z, a novel RT metallocarboxypeptidase."; RL J. Biol. Chem. 272:10543-10550(1997). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Teratocarcinoma; 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3), AND VARIANTS RP PRO-5 AND THR-486. RC TISSUE=Muscle; 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 [5] RP ENZYME ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=10080937; DOI=10.1006/bbrc.1999.0378; RA Novikova E.G., Fricker L.D.; RT "Purification and characterization of human metallocarboxypeptidase Z."; RL Biochem. Biophys. Res. Commun. 256:564-568(1999). RN [6] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=10671522; DOI=10.1074/jbc.275.7.4865; RA Novikova E.G., Reznik S.E., Varlamov O., Fricker L.D.; RT "Carboxypeptidase Z is present in the regulated secretory pathway and RT extracellular matrix in cultured cells and in human tissues."; RL J. Biol. Chem. 275:4865-4870(2000). RN [7] RP FUNCTION. RX PubMed=11766880; DOI=10.1007/pl00000819; RA Reznik S.E., Fricker L.D.; RT "Carboxypeptidases from A to Z: implications in embryonic development and RT Wnt binding."; RL Cell. Mol. Life Sci. 58:1790-1804(2001). RN [8] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=12417617; DOI=10.1177/002215540205001111; RA Fan X., Olson S.J., Blevins L.S., Allen G.S., Johnson M.D.; RT "Immunohistochemical localization of carboxypeptidases D, E, and Z in RT pituitary adenomas and normal human pituitary."; RL J. Histochem. Cytochem. 50:1509-1516(2002). CC -!- FUNCTION: Cleaves substrates with C-terminal arginine residues. CC Probably modulates the Wnt signaling pathway, by cleaving some CC undefined protein. May play a role in cleavage during prohormone CC processing. {ECO:0000269|PubMed:11766880, ECO:0000269|PubMed:12417617, CC ECO:0000269|PubMed:9099699}. CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000250|UniProtKB:P00730}; CC -!- ACTIVITY REGULATION: Inhibited by 2-mercaptomethyl-3- CC guanidinoethylthiopropanoic acid (MGTA) and CC guanidinoethylmercaptosuccinic acid (GEMSA). Inhibited by chelating CC agents such as EDTA and EGTA. {ECO:0000269|PubMed:9099699}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=2 mM for dansyl-Phe-Ala-Arg {ECO:0000269|PubMed:10080937, CC ECO:0000269|PubMed:9099699}; CC KM=2 mM for dansyl-Pro-Ala-Arg {ECO:0000269|PubMed:10080937, CC ECO:0000269|PubMed:9099699}; CC pH dependence: CC Optimum pH is 7.8. {ECO:0000269|PubMed:10080937, CC ECO:0000269|PubMed:9099699}; CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular CC matrix {ECO:0000269|PubMed:10671522}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q66K79-1; Sequence=Displayed; CC Name=2; CC IsoId=Q66K79-2; Sequence=VSP_020983; CC Name=3; CC IsoId=Q66K79-3; Sequence=VSP_040356; CC -!- TISSUE SPECIFICITY: In placenta, it is present within invasive CC trophoblasts and in the surrounding extracellular space. Also present CC in amnion cells, but is not readily apparent in the extracellular CC matrix of this cell type. Present in normal pituitary gland and CC neoplastic pituitary gland (especially POMC-, GH- and PRL-producing CC adenomas) (at protein level). Widely expressed. CC {ECO:0000269|PubMed:10671522, ECO:0000269|PubMed:12417617, CC ECO:0000269|PubMed:9099699}. CC -!- SIMILARITY: Belongs to the peptidase M14 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAB71147.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U83411; AAB58911.1; -; mRNA. DR EMBL; AK056317; BAB71147.1; ALT_FRAME; mRNA. DR EMBL; AC105345; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC006393; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; BC080539; AAH80539.1; -; mRNA. DR CCDS; CCDS33953.1; -. [Q66K79-1] DR CCDS; CCDS3404.1; -. [Q66K79-2] DR CCDS; CCDS43212.1; -. [Q66K79-3] DR RefSeq; NP_001014447.1; NM_001014447.2. [Q66K79-1] DR RefSeq; NP_001014448.1; NM_001014448.2. [Q66K79-3] DR RefSeq; NP_003643.2; NM_003652.3. [Q66K79-2] DR AlphaFoldDB; Q66K79; -. DR SMR; Q66K79; -. DR BioGRID; 114102; 23. DR IntAct; Q66K79; 3. DR STRING; 9606.ENSP00000354255; -. DR MEROPS; M14.012; -. DR GlyCosmos; Q66K79; 1 site, No reported glycans. DR GlyGen; Q66K79; 1 site. DR iPTMnet; Q66K79; -. DR PhosphoSitePlus; Q66K79; -. DR BioMuta; CPZ; -. DR DMDM; 296434423; -. DR EPD; Q66K79; -. DR jPOST; Q66K79; -. DR MassIVE; Q66K79; -. DR PaxDb; 9606-ENSP00000354255; -. DR PeptideAtlas; Q66K79; -. DR ProteomicsDB; 65958; -. [Q66K79-1] DR ProteomicsDB; 65959; -. [Q66K79-2] DR ProteomicsDB; 65960; -. [Q66K79-3] DR Antibodypedia; 22804; 72 antibodies from 23 providers. DR DNASU; 8532; -. DR Ensembl; ENST00000315782.6; ENSP00000315074.6; ENSG00000109625.19. [Q66K79-2] DR Ensembl; ENST00000360986.9; ENSP00000354255.4; ENSG00000109625.19. [Q66K79-1] DR Ensembl; ENST00000382480.6; ENSP00000371920.2; ENSG00000109625.19. [Q66K79-3] DR GeneID; 8532; -. DR KEGG; hsa:8532; -. DR MANE-Select; ENST00000360986.9; ENSP00000354255.4; NM_001014447.3; NP_001014447.2. DR UCSC; uc003glm.4; human. [Q66K79-1] DR AGR; HGNC:2333; -. DR CTD; 8532; -. DR DisGeNET; 8532; -. DR GeneCards; CPZ; -. DR HGNC; HGNC:2333; CPZ. DR HPA; ENSG00000109625; Tissue enhanced (ovary). DR MIM; 603105; gene. DR neXtProt; NX_Q66K79; -. DR OpenTargets; ENSG00000109625; -. DR PharmGKB; PA26854; -. DR VEuPathDB; HostDB:ENSG00000109625; -. DR eggNOG; KOG2649; Eukaryota. DR GeneTree; ENSGT00940000156391; -. DR HOGENOM; CLU_006722_5_1_1; -. DR InParanoid; Q66K79; -. DR OMA; VEAWPNK; -. DR OrthoDB; 5490979at2759; -. DR PhylomeDB; Q66K79; -. DR TreeFam; TF315592; -. DR PathwayCommons; Q66K79; -. DR SignaLink; Q66K79; -. DR BioGRID-ORCS; 8532; 12 hits in 1144 CRISPR screens. DR GeneWiki; CPZ_(gene); -. DR GenomeRNAi; 8532; -. DR Pharos; Q66K79; Tbio. DR PRO; PR:Q66K79; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q66K79; Protein. DR Bgee; ENSG00000109625; Expressed in left ovary and 99 other cell types or tissues. DR ExpressionAtlas; Q66K79; baseline and differential. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0004181; F:metallocarboxypeptidase activity; IBA:GO_Central. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0006518; P:peptide metabolic process; IBA:GO_Central. DR GO; GO:0016485; P:protein processing; IBA:GO_Central. DR GO; GO:0006508; P:proteolysis; TAS:ProtInc. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd07447; CRD_Carboxypeptidase_Z; 1. DR CDD; cd03867; M14_CPZ; 1. DR CDD; cd11308; Peptidase_M14NE-CP-C_like; 1. DR Gene3D; 2.60.40.1120; Carboxypeptidase-like, regulatory domain; 1. DR Gene3D; 1.10.2000.10; Frizzled cysteine-rich domain; 1. DR Gene3D; 3.40.630.10; Zn peptidases; 1. DR InterPro; IPR008969; CarboxyPept-like_regulatory. DR InterPro; IPR020067; Frizzled_dom. DR InterPro; IPR036790; Frizzled_dom_sf. DR InterPro; IPR034239; M14_CPZ_CPD. DR InterPro; IPR000834; Peptidase_M14. DR PANTHER; PTHR11532:SF63; CARBOXYPEPTIDASE Z; 1. DR PANTHER; PTHR11532; PROTEASE M14 CARBOXYPEPTIDASE; 1. DR Pfam; PF13620; CarboxypepD_reg; 1. DR Pfam; PF01392; Fz; 1. DR Pfam; PF00246; Peptidase_M14; 1. DR PRINTS; PR00765; CRBOXYPTASEA. DR SMART; SM00063; FRI; 1. DR SMART; SM00631; Zn_pept; 1. DR SUPFAM; SSF49464; Carboxypeptidase regulatory domain-like; 1. DR SUPFAM; SSF63501; Frizzled cysteine-rich domain; 1. DR SUPFAM; SSF53187; Zn-dependent exopeptidases; 1. DR PROSITE; PS00133; CARBOXYPEPT_ZN_2; 1. DR PROSITE; PS50038; FZ; 1. DR PROSITE; PS52035; PEPTIDASE_M14; 1. DR Genevisible; Q66K79; HS. PE 1: Evidence at protein level; KW Alternative splicing; Carboxypeptidase; Disulfide bond; KW Extracellular matrix; Glycoprotein; Hydrolase; Metal-binding; KW Metalloprotease; Protease; Reference proteome; Secreted; Signal; KW Wnt signaling pathway; Zinc. FT SIGNAL 1..18 FT /evidence="ECO:0000255" FT CHAIN 19..652 FT /note="Carboxypeptidase Z" FT /evidence="ECO:0000250" FT /id="PRO_0000252456" FT DOMAIN 27..160 FT /note="FZ" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090" FT DOMAIN 186..502 FT /note="Peptidase M14" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01379" FT REGION 595..629 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 472 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01379" FT BINDING 248 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01379" FT BINDING 251 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01379" FT BINDING 380 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01379" FT CARBOHYD 281 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 43..109 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090" FT DISULFID 51..102 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090" FT DISULFID 93..129 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090" FT DISULFID 118..157 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090" FT DISULFID 122..146 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00090" FT VAR_SEQ 1..137 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_040356" FT VAR_SEQ 30..40 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:9099699" FT /id="VSP_020983" FT VARIANT 5 FT /note="L -> P (in dbSNP:rs2302583)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:9099699" FT /id="VAR_027883" FT VARIANT 6 FT /note="P -> L (in dbSNP:rs34964084)" FT /evidence="ECO:0000269|PubMed:9099699" FT /id="VAR_047244" FT VARIANT 130 FT /note="Q -> L (in dbSNP:rs35993494)" FT /id="VAR_047245" FT VARIANT 486 FT /note="I -> T (in dbSNP:rs7378066)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:9099699" FT /id="VAR_047246" FT VARIANT 501 FT /note="T -> M (in dbSNP:rs9991535)" FT /id="VAR_027884" FT CONFLICT 200 FT /note="T -> M (in Ref. 4; BC006393)" FT /evidence="ECO:0000305" FT CONFLICT 291 FT /note="M -> I (in Ref. 1; AAB58911)" FT /evidence="ECO:0000305" FT CONFLICT 523 FT /note="I -> T (in Ref. 2; BAB71147)" FT /evidence="ECO:0000305" SQ SEQUENCE 652 AA; 73655 MW; BFA1EA7753E63F98 CRC64; MPPPLPLLLL TVLVVAAARP GCEFERNPAG ECHRPPAADS ATCVDLQLRT CSDAAYNHTT FPNLLQHRSW EVVEASSEYI LLSVLHQLLE GQCNPDLRLL GCAVLAPRCE GGWVRRPCRH ICEGLREVCQ PAFDAIDMAW PYFLDCHRYF TREDEGCYDP LEKLRGGLEA DEALPSGLPP TFIRFSHHSY AQMVRVLRRT ASRCAHVART YSIGRSFDGR ELLVIEFSSR PGQHELMEPE VKLIGNIHGN EVAGREMLIY LAQYLCSEYL LGNPRIQRLL NTTRIHLLPS MNPDGYEVAA AEGAGYNGWT SGRQNAQNLD LNRNFPDLTS EYYRLAETRG ARSDHIPIPQ HYWWGKVAPE TKAIMKWMQT IPFVLSASLH GGDLVVSYPF DFSKHPQEEK MFSPTPDEKM FKLLSRAYAD VHPMMMDRSE NRCGGNFLKR GSIINGADWY SFTGGMSDFN YLHTNCFEIT VELGCVKFPP EEALYILWQH NKESLLNFVE TVHRGIKGVV TDKFGKPVKN ARISVKGIRH DITTAPDGDY WRLLPPGIHI VIAQAPGYAK VIKKVIIPAR MKRAGRVDFI LQPLGMGPKN FIHGLRRTGP HDPLGGASSL GEATEPDPLR ARRQPSADGS KPWWWSYFTS LSTHRPRWLL KY //