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CBPE_HUMAN
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   03-AUG-2022, entry version 211.
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 IDDHH, AND VARIANT IDDHH 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 IDDHH 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: Intellectual developmental disorder and hypogonadotropic
CC       hypogonadism (IDDHH) [MIM:619326]: An autosomal recessive disorder
CC       characterized by obesity, intellectual disability, and hypogonadotropic
CC       hypogonadism. Additional variable features include central
CC       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};
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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; 43.
DR   IntAct; P16870; 21.
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   GlyGen; P16870; 2 sites, 16 N-linked glycans (2 sites).
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; P16870; -.
DR   PeptideAtlas; P16870; -.
DR   PRIDE; P16870; -.
DR   ProteomicsDB; 53394; -. [P16870-1]
DR   ProteomicsDB; 53395; -. [P16870-2]
DR   Antibodypedia; 16998; 360 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   CTD; 1363; -.
DR   DisGeNET; 1363; -.
DR   GeneCards; CPE; -.
DR   HGNC; HGNC:2303; CPE.
DR   HPA; ENSG00000109472; Tissue enhanced (brain, retina).
DR   MIM; 114855; gene.
DR   MIM; 619326; phenotype.
DR   neXtProt; NX_P16870; -.
DR   OpenTargets; ENSG00000109472; -.
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; 101221at2759; -.
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   BioGRID-ORCS; 1363; 14 hits in 1085 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 202 other tissues.
DR   ExpressionAtlas; P16870; baseline and differential.
DR   Genevisible; P16870; HS.
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   InterPro; IPR008969; CarboxyPept-like_regulatory.
DR   InterPro; IPR034232; M14_CPE_CPD.
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   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   ACT_SITE        342
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:P14384"
FT   BINDING         114
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:P00730"
FT   BINDING         117
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:P00730"
FT   BINDING         248
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:P00730"
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 IDDHH)"
FT                   /evidence="ECO:0000269|PubMed:34383079"
FT                   /id="VAR_085993"
FT   VARIANT         135..476
FT                   /note="Missing (in IDDHH)"
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
 
 
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