ID CBPE_HUMAN Reviewed; 476 AA. AC P16870; A8K4N1; B3KR42; B4DFN4; D3DP33; Q9UIU9; DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1990, sequence version 1. DT 24-JAN-2024, entry version 219. DE RecName: Full=Carboxypeptidase E; DE Short=CPE; DE EC=3.4.17.10; DE AltName: Full=Carboxypeptidase H; DE Short=CPH; DE AltName: Full=Enkephalin convertase; DE AltName: Full=Prohormone-processing carboxypeptidase; DE Flags: Precursor; GN Name=CPE; 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 1). RC TISSUE=Brain; RX PubMed=2334405; DOI=10.1042/bj2670517; RA Manser E., Fernandez D., Loo L., Goh P.Y., Monfries C., Hall C., Lim L.; RT "Human carboxypeptidase E. Isolation and characterization of the cDNA, RT sequence conservation, expression and processing in vitro."; RL Biochem. J. 267:517-525(1990). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9662053; DOI=10.1007/s001250050971; RA Utsunomiya N., Ohagi S., Sanke T., Tatsuta H., Hanabusa T., Nanjo K.; RT "Organization of the human carboxypeptidase E gene and molecular scanning RT for mutations in Japanese subjects with NIDDM or obesity."; RL Diabetologia 41:701-705(1998). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Amygdala, and 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 [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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Colon, and Eye; 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 RETRACTED PAPER. RX PubMed=21285511; DOI=10.1172/jci40433; RA Lee T.K., Murthy S.R., Cawley N.X., Dhanvantari S., Hewitt S.M., Lou H., RA Lau T., Ma S., Huynh T., Wesley R.A., Ng I.O., Pacak K., Poon R.T., RA Loh Y.P.; RT "An N-terminal truncated carboxypeptidase E splice isoform induces tumor RT growth and is a biomarker for predicting future metastasis in human RT cancers."; RL J. Clin. Invest. 121:880-892(2011). RN [7] RP RETRACTION NOTICE OF PUBMED:21285511. RX PubMed=30882370; DOI=10.1172/jci128836; RA Lee T.K., Murthy S.R., Cawley N.X., Dhanvantari S., Hewitt S.M., Lou H., RA Lau T., Ma S., Huynh T., Wesley R.A., Ng I.O., Pacak K., Poon R.T., RA Loh Y.P.; RL J. Clin. Invest. 130:1804-1804(2019). RN [8] RP INVOLVEMENT IN BDVS, AND VARIANT BDVS 121-ARG--PHE-476 DEL. RX PubMed=34383079; DOI=10.1210/clinem/dgab592; RA Bosch E., Hebebrand M., Popp B., Penger T., Behring B., Cox H., Towner S., RA Kraus C., Wilson W.G., Khan S., Krumbiegel M., Ekici A.B., Uebe S., RA Trollmann R., Woelfle J., Reis A., Vasileiou G.; RT "BDV syndrome: An emerging syndrome with profound obesity and RT neurodevelopmental delay resembling Prader-Willi syndrome."; RL J. Clin. Endocrinol. Metab. 106:3413-3427(2021). RN [9] RP VARIANT BDVS 135-TYR--PHE-476 DEL. RX PubMed=32936766; DOI=10.4274/jcrpe.galenos.2020.2020.0101; RA Durmaz A., Aykut A., Atik T., Oezen S., Ayyildiz Emecen D., Ata A., RA Isik E., Goeksen D., Cogulu O., Oezkinay F.; RT "A new cause of obesity syndrome associated with a mutation in the RT carboxypeptidase gene detected in three siblings with obesity, intellectual RT disability and hypogonadotropic hypogonadism."; RL J. Clin. Res. Pediatr. Endocrinol. 13:52-60(2021). RN [10] RP VARIANT [LARGE SCALE ANALYSIS] GLN-297. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Sorting receptor that directs prohormones to the regulated CC secretory pathway. Acts also as a prohormone processing enzyme in CC neuro/endocrine cells, removing dibasic residues from the C-terminal CC end of peptide hormone precursors after initial endoprotease cleavage. CC {ECO:0000250|UniProtKB:Q00493}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Release of C-terminal arginine or lysine residues from CC polypeptides.; EC=3.4.17.10; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000250|UniProtKB:P00730}; CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P00730}; CC -!- SUBUNIT: Interacts with secretogranin III/SCG3. CC {ECO:0000250|UniProtKB:Q00493}. CC -!- INTERACTION: CC P16870; P49768-2: PSEN1; NbExp=3; IntAct=EBI-711320, EBI-11047108; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasmic vesicle, secretory CC vesicle {ECO:0000250|UniProtKB:Q00493}. Cytoplasmic vesicle, secretory CC vesicle membrane {ECO:0000250|UniProtKB:P15087}; Peripheral membrane CC protein {ECO:0000250|UniProtKB:P15087}. Secreted CC {ECO:0000250|UniProtKB:P15087}. Note=Associated with the secretory CC granule membrane through direct binding to lipid rafts in intragranular CC conditions. {ECO:0000250|UniProtKB:Q00493}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P16870-1; Sequence=Displayed; CC Name=2; Synonyms=CPE delta-N; CC IsoId=P16870-2; Sequence=VSP_040959; CC -!- DISEASE: BDV syndrome (BDVS) [MIM:619326]: An autosomal recessive CC disorder characterized by obesity, intellectual disability, and CC hypogonadotropic hypogonadism. Additional variable features include CC central hypothyroidism, hypotonia, and developmental delay. CC {ECO:0000269|PubMed:32936766, ECO:0000269|PubMed:34383079}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the peptidase M14 family. {ECO:0000305}. CC -!- CAUTION: Isoform 2 was reported to be located in the nucleus and to CC interact with HDAC1 and HDAC2 (PubMed:21285511). However, this work was CC later retracted (PubMed:30882370). {ECO:0000305|PubMed:21285511, CC ECO:0000305|PubMed:30882370}. CC -!- SEQUENCE CAUTION: CC Sequence=BAG52254.1; 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; X51405; CAA35767.1; -; mRNA. DR EMBL; AB006898; BAA86053.1; -; Genomic_DNA. DR EMBL; AK090962; BAG52254.1; ALT_FRAME; mRNA. DR EMBL; AK290996; BAF83685.1; -; mRNA. DR EMBL; AK294175; BAG57495.1; -; mRNA. DR EMBL; CH471056; EAX04817.1; -; Genomic_DNA. DR EMBL; CH471056; EAX04818.1; -; Genomic_DNA. DR EMBL; BC033866; AAH33866.1; -; mRNA. DR EMBL; BC053612; AAH53612.1; -; mRNA. DR CCDS; CCDS3810.1; -. [P16870-1] DR PIR; S09489; S09489. DR RefSeq; NP_001864.1; NM_001873.3. [P16870-1] DR AlphaFoldDB; P16870; -. DR SMR; P16870; -. DR BioGRID; 107755; 44. DR IntAct; P16870; 22. DR STRING; 9606.ENSP00000386104; -. DR DrugBank; DB00030; Insulin human. DR DrugBank; DB14487; Zinc acetate. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR MEROPS; M14.005; -. DR GlyConnect; 1067; 1 N-Linked glycan (1 site). DR GlyCosmos; P16870; 2 sites, 6 glycans. DR GlyGen; P16870; 3 sites, 16 N-linked glycans (2 sites), 1 O-linked glycan (1 site). DR iPTMnet; P16870; -. DR PhosphoSitePlus; P16870; -. DR BioMuta; CPE; -. DR DMDM; 115892; -. DR CPTAC; CPTAC-1486; -. DR EPD; P16870; -. DR jPOST; P16870; -. DR MassIVE; P16870; -. DR MaxQB; P16870; -. DR PaxDb; 9606-ENSP00000386104; -. DR PeptideAtlas; P16870; -. DR PRIDE; P16870; -. DR ProteomicsDB; 53394; -. [P16870-1] DR ProteomicsDB; 53395; -. [P16870-2] DR Pumba; P16870; -. DR Antibodypedia; 16998; 388 antibodies from 36 providers. DR DNASU; 1363; -. DR Ensembl; ENST00000402744.9; ENSP00000386104.4; ENSG00000109472.14. [P16870-1] DR GeneID; 1363; -. DR KEGG; hsa:1363; -. DR MANE-Select; ENST00000402744.9; ENSP00000386104.4; NM_001873.4; NP_001864.1. DR UCSC; uc003irg.5; human. [P16870-1] DR AGR; HGNC:2303; -. DR CTD; 1363; -. DR DisGeNET; 1363; -. DR GeneCards; CPE; -. DR HGNC; HGNC:2303; CPE. DR HPA; ENSG00000109472; Tissue enhanced (brain, retina). DR MalaCards; CPE; -. DR MIM; 114855; gene. DR MIM; 619326; phenotype. DR neXtProt; NX_P16870; -. DR OpenTargets; ENSG00000109472; -. DR Orphanet; 633028; CPE-related Prader-Willi-like syndrome. DR PharmGKB; PA26824; -. DR VEuPathDB; HostDB:ENSG00000109472; -. DR eggNOG; KOG2649; Eukaryota. DR GeneTree; ENSGT00940000157158; -. DR HOGENOM; CLU_006722_1_3_1; -. DR InParanoid; P16870; -. DR OMA; WEQNRDS; -. DR OrthoDB; 5490979at2759; -. DR PhylomeDB; P16870; -. DR TreeFam; TF315592; -. DR BRENDA; 3.4.17.10; 2681. DR PathwayCommons; P16870; -. DR Reactome; R-HSA-264876; Insulin processing. DR SignaLink; P16870; -. DR SIGNOR; P16870; -. DR BioGRID-ORCS; 1363; 16 hits in 1165 CRISPR screens. DR ChiTaRS; CPE; human. DR GeneWiki; Carboxypeptidase_E; -. DR GenomeRNAi; 1363; -. DR Pharos; P16870; Tbio. DR PRO; PR:P16870; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P16870; Protein. DR Bgee; ENSG00000109472; Expressed in type B pancreatic cell and 204 other cell types or tissues. DR ExpressionAtlas; P16870; baseline and differential. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0005794; C:Golgi apparatus; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc. DR GO; GO:0030667; C:secretory granule membrane; IEA:Ensembl. DR GO; GO:0030658; C:transport vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0004180; F:carboxypeptidase activity; TAS:ProtInc. DR GO; GO:0050839; F:cell adhesion molecule binding; IPI:BHF-UCL. DR GO; GO:0004181; F:metallocarboxypeptidase activity; IBA:GO_Central. DR GO; GO:0042043; F:neurexin family protein binding; IPI:BHF-UCL. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0003214; P:cardiac left ventricle morphogenesis; IMP:BHF-UCL. DR GO; GO:0030070; P:insulin processing; IEA:Ensembl. DR GO; GO:0007218; P:neuropeptide signaling pathway; NAS:UniProtKB. DR GO; GO:0030072; P:peptide hormone secretion; IEA:Ensembl. DR GO; GO:0006518; P:peptide metabolic process; IBA:GO_Central. DR GO; GO:0072657; P:protein localization to membrane; IDA:BHF-UCL. DR GO; GO:0033366; P:protein localization to secretory granule; IEA:Ensembl. DR GO; GO:0036211; P:protein modification process; NAS:UniProtKB. DR GO; GO:0016485; P:protein processing; IBA:GO_Central. DR GO; GO:0016055; P:Wnt signaling pathway; IDA:CACAO. DR CDD; cd03865; M14_CPE; 1. DR CDD; cd11308; Peptidase_M14NE-CP-C_like; 1. DR Gene3D; 2.60.40.1120; Carboxypeptidase-like, regulatory domain; 1. DR Gene3D; 3.40.630.10; Zn peptidases; 1. DR InterPro; IPR008969; CarboxyPept-like_regulatory. DR InterPro; IPR034232; M14_CPE_CPD. DR InterPro; IPR000834; Peptidase_M14. DR PANTHER; PTHR11532:SF92; CARBOXYPEPTIDASE E; 1. DR PANTHER; PTHR11532; PROTEASE M14 CARBOXYPEPTIDASE; 1. DR Pfam; PF13620; CarboxypepD_reg; 1. DR Pfam; PF00246; Peptidase_M14; 1. DR PRINTS; PR00765; CRBOXYPTASEA. DR SMART; SM00631; Zn_pept; 1. DR SUPFAM; SSF49464; Carboxypeptidase regulatory domain-like; 1. DR SUPFAM; SSF53187; Zn-dependent exopeptidases; 1. DR PROSITE; PS00132; CARBOXYPEPT_ZN_1; 1. DR PROSITE; PS00133; CARBOXYPEPT_ZN_2; 1. DR PROSITE; PS52035; PEPTIDASE_M14; 1. DR Genevisible; P16870; HS. PE 1: Evidence at protein level; KW Alternative splicing; Carboxypeptidase; Cleavage on pair of basic residues; KW Cytoplasmic vesicle; Disease variant; Glycoprotein; Hydrolase; KW Hypogonadotropic hypogonadism; Intellectual disability; Membrane; KW Metal-binding; Metalloprotease; Obesity; Protease; Reference proteome; KW Secreted; Signal; Zinc; Zymogen. FT SIGNAL 1..25 FT /evidence="ECO:0000255" FT PROPEP 26..42 FT /note="Activation peptide" FT /id="PRO_0000004384" FT CHAIN 43..476 FT /note="Carboxypeptidase E" FT /id="PRO_0000004385" FT DOMAIN 52..372 FT /note="Peptidase M14" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01379" FT ACT_SITE 342 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01379" FT BINDING 114 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01379" FT BINDING 117 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_note="catalytic" 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 CARBOHYD 139 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 390 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..36 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_040959" FT VARIANT 121..476 FT /note="Missing (in BDVS)" FT /evidence="ECO:0000269|PubMed:34383079" FT /id="VAR_085993" FT VARIANT 135..476 FT /note="Missing (in BDVS)" FT /evidence="ECO:0000269|PubMed:32936766" FT /id="VAR_085994" FT VARIANT 235 FT /note="W -> R (in dbSNP:rs34516004)" FT /id="VAR_048599" FT VARIANT 297 FT /note="R -> Q (in a colorectal cancer sample; somatic FT mutation; dbSNP:rs541147146)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036011" FT CONFLICT 287 FT /note="S -> P (in Ref. 3; BAG52254)" FT /evidence="ECO:0000305" FT CONFLICT 391 FT /note="A -> R (in Ref. 2; BAA86053)" FT /evidence="ECO:0000305" SQ SEQUENCE 476 AA; 53151 MW; D561AC0285A51E86 CRC64; MAGRGGSALL ALCGALAACG WLLGAEAQEP GAPAAGMRRR RRLQQEDGIS FEYHRYPELR EALVSVWLQC TAISRIYTVG RSFEGRELLV IELSDNPGVH EPGEPEFKYI GNMHGNEAVG RELLIFLAQY LCNEYQKGNE TIVNLIHSTR IHIMPSLNPD GFEKAASQPG ELKDWFVGRS NAQGIDLNRN FPDLDRIVYV NEKEGGPNNH LLKNMKKIVD QNTKLAPETK AVIHWIMDIP FVLSANLHGG DLVANYPYDE TRSGSAHEYS SSPDDAIFQS LARAYSSFNP AMSDPNRPPC RKNDDDSSFV DGTTNGGAWY SVPGGMQDFN YLSSNCFEIT VELSCEKFPP EETLKTYWED NKNSLISYLE QIHRGVKGFV RDLQGNPIAN ATISVEGIDH DVTSAKDGDY WRLLIPGNYK LTASAPGYLA ITKKVAVPYS PAAGVDFELE SFSERKEEEK EELMEWWKMM SETLNF //