CBPA6_HUMAN
ID CBPA6_HUMAN Reviewed; 437 AA.
AC Q8N4T0; Q8NEX8; Q8TDE8; Q9NRI9;
DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot.
DT 24-JAN-2006, sequence version 2.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Carboxypeptidase A6;
DE EC=3.4.17.-;
DE Flags: Precursor;
GN Name=CPA6; Synonyms=CPAH;
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 [GENOMIC DNA / MRNA] (ISOFORM 1).
RX PubMed=11836249; DOI=10.1074/jbc.m112254200;
RA Wei S., Segura S., Vendrell J., Aviles F.X., Lanoue E., Day R., Feng Y.,
RA Fricker L.D.;
RT "Identification and characterization of three members of the human
RT metallocarboxypeptidase gene family.";
RL J. Biol. Chem. 277:14954-14964(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND CHROMOSOMAL TRANSLOCATION.
RC TISSUE=Retina;
RX PubMed=12454025;
RA Pizzuti A., Calabrese G., Bozzali M., Telvi L., Morizio E., Guida V.,
RA Gatta V., Stuppia L., Ion A., Palka G., Dallapiccola B.;
RT "A peptidase gene in chromosome 8q is disrupted by a balanced translocation
RT in a duane syndrome patient.";
RL Invest. Ophthalmol. Vis. Sci. 43:3609-3612(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT CYS-173.
RC TISSUE=Hematopoietic stem cell;
RA Gu J., Huang Q., Yu Y., Xu S., Han Z., Fu G., Chen Z.;
RT "Novel genes expressed in hematopoietic stem/progenitor cells from
RT myelodysplastic syndrome patients.";
RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT CYS-173.
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 [5]
RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND SUBSTRATE
RP SPECIFICITY.
RX PubMed=18178555; DOI=10.1074/jbc.m707680200;
RA Lyons P.J., Callaway M.B., Fricker L.D.;
RT "Characterization of carboxypeptidase A6, an extracellular matrix
RT peptidase.";
RL J. Biol. Chem. 283:7054-7063(2008).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=20855895; DOI=10.1074/jbc.m110.158626;
RA Lyons P.J., Fricker L.D.;
RT "Substrate specificity of human carboxypeptidase A6.";
RL J. Biol. Chem. 285:38234-38242(2010).
RN [7]
RP TISSUE SPECIFICITY, VARIANT ETL5 ARG-267, VARIANT FEB11 VAL-270,
RP CHARACTERIZATION OF VARIANT ETL5 ARG-267, AND CHARACTERIZATION OF VARIANT
RP FEB11 VAL-270.
RX PubMed=21922598; DOI=10.1002/humu.21613;
RA Salzmann A., Guipponi M., Lyons P.J., Fricker L.D., Sapio M., Lambercy C.,
RA Buresi C., Bencheikh B.O., Lahjouji F., Ouazzani R., Crespel A.,
RA Chaigne D., Malafosse A.;
RT "Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of
RT febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe
RT epilepsy.";
RL Hum. Mutat. 33:124-135(2012).
CC -!- FUNCTION: May be involved in the proteolytic inactivation of
CC enkephalins and neurotensin in some brain areas. May convert inactive
CC angiotensin I into the biologically active angiotensin II
CC (PubMed:18178555). Releases a C-terminal amino acid, with preference
CC for large hydrophobic C-terminal amino acids and shows only very weak
CC activity toward small amino acids and histidine (PubMed:20855895).
CC {ECO:0000269|PubMed:18178555, ECO:0000269|PubMed:20855895}.
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 -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=266 uM for 3-(2-furyl)acryloyl-Phe-Phe
CC {ECO:0000269|PubMed:20855895};
CC KM=100 uM for 3-(2-furyl)acryloyl-Phe-Tyr
CC {ECO:0000269|PubMed:20855895};
CC KM=386 uM for 3-(2-furyl)acryloyl-Phe-Leu
CC {ECO:0000269|PubMed:20855895};
CC KM=339 uM for 3-(2-furyl)acryloyl-Phe-Trp
CC {ECO:0000269|PubMed:20855895};
CC KM=786 uM for 3-(2-furyl)acryloyl-Phe-Met
CC {ECO:0000269|PubMed:20855895};
CC pH dependence:
CC Optimum pH is 8. {ECO:0000269|PubMed:20855895};
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix {ECO:0000269|PubMed:18178555}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8N4T0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8N4T0-2; Sequence=VSP_008808;
CC Name=3;
CC IsoId=Q8N4T0-3; Sequence=VSP_058375, VSP_058376;
CC -!- TISSUE SPECIFICITY: Expressed in the hippocampus, nucleus raphe, and
CC cortex. {ECO:0000269|PubMed:21922598}.
CC -!- DISEASE: Note=A chromosomal aberration involving CPA6 was found in a
CC patient with Duane retraction syndrome. Translocation t(6;8)(q26;q13).
CC -!- DISEASE: Epilepsy, familial temporal lobe, 5 (ETL5) [MIM:614417]: A
CC focal form of epilepsy characterized by recurrent seizures that arise
CC from foci within the temporal lobe. Seizures are usually accompanied by
CC sensory symptoms, most often auditory in nature.
CC {ECO:0000269|PubMed:21922598}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Febrile seizures, familial, 11 (FEB11) [MIM:614418]: Seizures
CC associated with febrile episodes in childhood without any evidence of
CC intracranial infection or defined pathologic or traumatic cause. It is
CC a common condition, affecting 2-5% of children aged 3 months to 5
CC years. The majority are simple febrile seizures (generally defined as
CC generalized onset, single seizures with a duration of less than 30
CC minutes). Complex febrile seizures are characterized by focal onset,
CC duration greater than 30 minutes, and/or more than one seizure in a 24
CC hour period. The likelihood of developing epilepsy following simple
CC febrile seizures is low. Complex febrile seizures are associated with a
CC moderately increased incidence of epilepsy.
CC {ECO:0000269|PubMed:21922598}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 2]: May be due to intron retention.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase M14 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAK84941.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305};
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DR EMBL; AF466284; AAM19307.1; -; Genomic_DNA.
DR EMBL; BK000188; DAA00037.1; -; mRNA.
DR EMBL; AY044833; AAK84941.1; ALT_SEQ; mRNA.
DR EMBL; AF221594; AAF91231.1; -; mRNA.
DR EMBL; BC033684; AAH33684.1; -; mRNA.
DR CCDS; CCDS6200.1; -. [Q8N4T0-1]
DR RefSeq; NP_065094.3; NM_020361.4. [Q8N4T0-1]
DR AlphaFoldDB; Q8N4T0; -.
DR SMR; Q8N4T0; -.
DR BioGRID; 121362; 21.
DR IntAct; Q8N4T0; 12.
DR STRING; 9606.ENSP00000297770; -.
DR DrugBank; DB12668; Metenkefalin.
DR MEROPS; M14.018; -.
DR GlyGen; Q8N4T0; 4 sites, 1 O-linked glycan (1 site).
DR iPTMnet; Q8N4T0; -.
DR PhosphoSitePlus; Q8N4T0; -.
DR BioMuta; CPA6; -.
DR DMDM; 85683250; -.
DR EPD; Q8N4T0; -.
DR jPOST; Q8N4T0; -.
DR MassIVE; Q8N4T0; -.
DR PaxDb; Q8N4T0; -.
DR PeptideAtlas; Q8N4T0; -.
DR PRIDE; Q8N4T0; -.
DR ProteomicsDB; 71968; -. [Q8N4T0-1]
DR ProteomicsDB; 71969; -. [Q8N4T0-2]
DR ProteomicsDB; 71970; -. [Q8N4T0-3]
DR Antibodypedia; 42507; 176 antibodies from 25 providers.
DR DNASU; 57094; -.
DR Ensembl; ENST00000297770.10; ENSP00000297770.4; ENSG00000165078.13. [Q8N4T0-1]
DR Ensembl; ENST00000479862.6; ENSP00000419016.2; ENSG00000165078.13. [Q8N4T0-3]
DR Ensembl; ENST00000638254.1; ENSP00000491129.1; ENSG00000165078.13. [Q8N4T0-3]
DR GeneID; 57094; -.
DR KEGG; hsa:57094; -.
DR MANE-Select; ENST00000297770.10; ENSP00000297770.4; NM_020361.5; NP_065094.3.
DR UCSC; uc003xxq.5; human. [Q8N4T0-1]
DR CTD; 57094; -.
DR DisGeNET; 57094; -.
DR GeneCards; CPA6; -.
DR HGNC; HGNC:17245; CPA6.
DR HPA; ENSG00000165078; Tissue enhanced (intestine, prostate, retina).
DR MalaCards; CPA6; -.
DR MIM; 609562; gene.
DR MIM; 614417; phenotype.
DR MIM; 614418; phenotype.
DR neXtProt; NX_Q8N4T0; -.
DR OpenTargets; ENSG00000165078; -.
DR Orphanet; 163717; Benign familial mesial temporal lobe epilepsy.
DR Orphanet; 165805; Familial mesial temporal lobe epilepsy with febrile seizures.
DR PharmGKB; PA38444; -.
DR VEuPathDB; HostDB:ENSG00000165078; -.
DR eggNOG; KOG2650; Eukaryota.
DR GeneTree; ENSGT00940000159307; -.
DR HOGENOM; CLU_019326_0_3_1; -.
DR InParanoid; Q8N4T0; -.
DR OMA; HQHAREH; -.
DR OrthoDB; 524270at2759; -.
DR PhylomeDB; Q8N4T0; -.
DR TreeFam; TF317197; -.
DR PathwayCommons; Q8N4T0; -.
DR SignaLink; Q8N4T0; -.
DR BioGRID-ORCS; 57094; 15 hits in 1071 CRISPR screens.
DR ChiTaRS; CPA6; human.
DR GeneWiki; Carboxypeptidase_A6; -.
DR GenomeRNAi; 57094; -.
DR Pharos; Q8N4T0; Tbio.
DR PRO; PR:Q8N4T0; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q8N4T0; protein.
DR Bgee; ENSG00000165078; Expressed in buccal mucosa cell and 80 other tissues.
DR Genevisible; Q8N4T0; HS.
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:0006508; P:proteolysis; IBA:GO_Central.
DR CDD; cd03872; M14_CPA6; 1.
DR Gene3D; 3.30.70.340; -; 1.
DR InterPro; IPR033843; CPAH.
DR InterPro; IPR036990; M14A-like_propep.
DR InterPro; IPR003146; M14A_act_pep.
DR InterPro; IPR000834; Peptidase_M14.
DR Pfam; PF00246; Peptidase_M14; 1.
DR Pfam; PF02244; Propep_M14; 1.
DR PRINTS; PR00765; CRBOXYPTASEA.
DR SMART; SM00631; Zn_pept; 1.
DR PROSITE; PS00133; CARBOXYPEPT_ZN_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Carboxypeptidase; Chromosomal rearrangement;
KW Cleavage on pair of basic residues; Disease variant; Disulfide bond;
KW Epilepsy; Extracellular matrix; Glycoprotein; Hydrolase; Metal-binding;
KW Metalloprotease; Protease; Reference proteome; Secreted; Signal; Zinc;
KW Zymogen.
FT SIGNAL 1..30
FT /evidence="ECO:0000255"
FT PROPEP 31..129
FT /note="Activation peptide"
FT /evidence="ECO:0000250"
FT /id="PRO_0000004365"
FT CHAIN 130..437
FT /note="Carboxypeptidase A6"
FT /id="PRO_0000004366"
FT ACT_SITE 398
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:P00732"
FT BINDING 196..199
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00730"
FT BINDING 196
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00730"
FT BINDING 199
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00730"
FT BINDING 254
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00730"
FT BINDING 271..272
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00730"
FT BINDING 324
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000250|UniProtKB:P00730"
FT BINDING 325..326
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00730"
FT BINDING 376
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P00730"
FT CARBOHYD 89
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 153
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 427
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 265..288
FT /evidence="ECO:0000250|UniProtKB:Q96IY4"
FT VAR_SEQ 65..92
FT /note="VDLWQPSSISYVSEGTVTDVHIPQNGSR -> GPHRRSSENTGEGKQLAHPE
FT KPKIPLWI (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:12454025"
FT /id="VSP_058375"
FT VAR_SEQ 93..437
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:12454025"
FT /id="VSP_058376"
FT VAR_SEQ 280..437
FT /note="DEGASMHPCDDTYCGPFPESEPEVKAVANFLRKHRKHIRAYLSFHAYAQMLL
FT YPYSYKYATIPNFRCVESAAYKAVNALQSVYGVRYRYGPASTTLYVSSGSSMDWAYKNG
FT IPYAFAFELRDTGYFGFLLPEMLIKPTCTETMLAVKNITMHLLKKCP -> GKFGTNWD
FT PDPKVSAGFTLQNMSPEDSHGRLMFFCM (in isoform 2)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_008808"
FT VARIANT 45
FT /note="F -> L (in dbSNP:rs10957393)"
FT /id="VAR_024241"
FT VARIANT 173
FT /note="S -> C (in dbSNP:rs17853192)"
FT /evidence="ECO:0000269|PubMed:15489334, ECO:0000269|Ref.3"
FT /id="VAR_025003"
FT VARIANT 249
FT /note="N -> S (in dbSNP:rs17343819)"
FT /id="VAR_048597"
FT VARIANT 267
FT /note="G -> R (in ETL5; affects protein secretion
FT presumably by altering protein folding or stability;
FT dbSNP:rs61738009)"
FT /evidence="ECO:0000269|PubMed:21922598"
FT /id="VAR_066946"
FT VARIANT 270
FT /note="A -> V (in FEB11; affects protein secretion
FT presumably by altering protein folding or stability;
FT dbSNP:rs114402678)"
FT /evidence="ECO:0000269|PubMed:21922598"
FT /id="VAR_066947"
SQ SEQUENCE 437 AA; 51008 MW; 9C21780D4B7D0A98 CRC64;
MKCLGKRRGQ AAAFLPLCWL FLKILQPGHS HLYNNRYAGD KVIRFIPKTE EEAYALKKIS
YQLKVDLWQP SSISYVSEGT VTDVHIPQNG SRALLAFLQE ANIQYKVLIE DLQKTLEKGS
SLHTQRNRRS LSGYNYEVYH SLEEIQNWMH HLNKTHSGLI HMFSIGRSYE GRSLFILKLG
RRSRLKRAVW IDCGIHAREW IGPAFCQWFV KEALLTYKSD PAMRKMLNHL YFYIMPVFNV
DGYHFSWTND RFWRKTRSRN SRFRCRGVDA NRNWKVKWCD EGASMHPCDD TYCGPFPESE
PEVKAVANFL RKHRKHIRAY LSFHAYAQML LYPYSYKYAT IPNFRCVESA AYKAVNALQS
VYGVRYRYGP ASTTLYVSSG SSMDWAYKNG IPYAFAFELR DTGYFGFLLP EMLIKPTCTE
TMLAVKNITM HLLKKCP
