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Protein

Carboxypeptidase A6

Gene

CPA6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

May be involved in the proteolytic inactivation of enkephalins and neurotensin in some brain areas. May convert inactive angiotensin I into the biologically active angiotensin II.1 Publication

Catalytic activityi

Release of a C-terminal amino acid, with preference for large hydrophobic C-terminal amino acids and only very weak activity toward small amino acids and histidine.1 Publication

Cofactori

Zn2+By similarityNote: Binds 1 zinc ion per subunit.By similarity

Kineticsi

  1. KM=266 µM for 3-(2-furyl)acryloyl-Phe-Phe1 Publication
  2. KM=100 µM for 3-(2-furyl)acryloyl-Phe-Tyr1 Publication
  3. KM=386 µM for 3-(2-furyl)acryloyl-Phe-Leu1 Publication
  4. KM=339 µM for 3-(2-furyl)acryloyl-Phe-Trp1 Publication
  5. KM=786 µM for 3-(2-furyl)acryloyl-Phe-Met1 Publication

    pH dependencei

    Optimum pH is 8.1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Metal bindingi196 – 1961Zinc; catalyticBy similarity
    Metal bindingi199 – 1991Zinc; catalyticBy similarity
    Binding sitei254 – 2541SubstrateBy similarity
    Metal bindingi324 – 3241Zinc; catalyticBy similarity
    Active sitei398 – 3981NucleophileBy similarity

    GO - Molecular functioni

    • metallocarboxypeptidase activity Source: UniProtKB
    • zinc ion binding Source: InterPro
    Complete GO annotation...

    Keywords - Molecular functioni

    Carboxypeptidase, Hydrolase, Metalloprotease, Protease

    Keywords - Ligandi

    Metal-binding, Zinc

    Protein family/group databases

    MEROPSiM14.018.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Carboxypeptidase A6 (EC:3.4.17.-)
    Gene namesi
    Name:CPA6
    Synonyms:CPAH
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640 Componenti: Chromosome 8

    Organism-specific databases

    HGNCiHGNC:17245. CPA6.

    Subcellular locationi

    GO - Cellular componenti

    Complete GO annotation...

    Keywords - Cellular componenti

    Extracellular matrix, Secreted

    Pathology & Biotechi

    Involvement in diseasei

    A chromosomal aberration involving CPA6 was found in a patient with Duane retraction syndrome. Translocation t(6;8)(q26;q13).

    Epilepsy, familial temporal lobe, 5 (ETL5)1 Publication

    The disease is caused by mutations affecting the gene represented in this entry.

    Disease descriptionA focal form of epilepsy characterized by recurrent seizures that arise from foci within the temporal lobe. Seizures are usually accompanied by sensory symptoms, most often auditory in nature.

    See also OMIM:614417
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti267 – 2671G → R in ETL5; affects protein secretion presumably by altering protein folding or stability. 1 Publication
    VAR_066946
    Febrile seizures, familial, 11 (FEB11)1 Publication

    The disease is caused by mutations affecting the gene represented in this entry.

    Disease descriptionSeizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy.

    See also OMIM:614418
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti270 – 2701A → V in FEB11; affects protein secretion presumably by altering protein folding or stability. 1 Publication
    Corresponds to variant rs114402678 [ dbSNP | Ensembl ].
    VAR_066947

    Keywords - Diseasei

    Disease mutation, Epilepsy

    Organism-specific databases

    MIMi614417. phenotype.
    614418. phenotype.
    Orphaneti165805. Familial mesial temporal lobe epilepsy with febrile seizures.
    PharmGKBiPA38444.

    Polymorphism and mutation databases

    BioMutaiCPA6.
    DMDMi85683250.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 3030Sequence AnalysisAdd
    BLAST
    Propeptidei31 – 12999Activation peptideBy similarityPRO_0000004365Add
    BLAST
    Chaini130 – 437308Carboxypeptidase A6PRO_0000004366Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Glycosylationi89 – 891N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi153 – 1531N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi265 ↔ 288By similarity
    Glycosylationi427 – 4271N-linked (GlcNAc...)Sequence Analysis

    Keywords - PTMi

    Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Zymogen

    Proteomic databases

    PaxDbiQ8N4T0.
    PRIDEiQ8N4T0.

    PTM databases

    PhosphoSiteiQ8N4T0.

    Expressioni

    Tissue specificityi

    Expressed in the hippocampus, nucleus raphe, and cortex.1 Publication

    Gene expression databases

    BgeeiQ8N4T0.
    CleanExiHS_CPA6.
    ExpressionAtlasiQ8N4T0. baseline and differential.
    GenevisibleiQ8N4T0. HS.

    Interactioni

    Protein-protein interaction databases

    BioGridi121362. 18 interactions.
    STRINGi9606.ENSP00000297770.

    Structurei

    3D structure databases

    ProteinModelPortaliQ8N4T0.
    SMRiQ8N4T0. Positions 37-433.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni196 – 1994Substrate bindingBy similarity
    Regioni271 – 2722Substrate bindingBy similarity
    Regioni325 – 3262Substrate bindingBy similarity

    Sequence similaritiesi

    Belongs to the peptidase M14 family.Curated

    Keywords - Domaini

    Signal

    Phylogenomic databases

    eggNOGiCOG2866.
    GeneTreeiENSGT00760000119103.
    HOGENOMiHOG000252968.
    HOVERGENiHBG050815.
    InParanoidiQ8N4T0.
    KOiK08782.
    OMAiQLYFYIM.
    PhylomeDBiQ8N4T0.
    TreeFamiTF317197.

    Family and domain databases

    Gene3Di3.30.70.340. 1 hit.
    InterProiIPR000834. Peptidase_M14.
    IPR003146. Prot_inh_M14A.
    IPR009020. Prot_inh_propept.
    [Graphical view]
    PfamiPF00246. Peptidase_M14. 1 hit.
    PF02244. Propep_M14. 1 hit.
    [Graphical view]
    PRINTSiPR00765. CRBOXYPTASEA.
    SMARTiSM00631. Zn_pept. 1 hit.
    [Graphical view]
    SUPFAMiSSF54897. SSF54897. 1 hit.
    PROSITEiPS00133. CARBOXYPEPT_ZN_2. 1 hit.
    [Graphical view]

    Sequences (3)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: Q8N4T0-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MKCLGKRRGQ AAAFLPLCWL FLKILQPGHS HLYNNRYAGD KVIRFIPKTE
    60 70 80 90 100
    EEAYALKKIS YQLKVDLWQP SSISYVSEGT VTDVHIPQNG SRALLAFLQE
    110 120 130 140 150
    ANIQYKVLIE DLQKTLEKGS SLHTQRNRRS LSGYNYEVYH SLEEIQNWMH
    160 170 180 190 200
    HLNKTHSGLI HMFSIGRSYE GRSLFILKLG RRSRLKRAVW IDCGIHAREW
    210 220 230 240 250
    IGPAFCQWFV KEALLTYKSD PAMRKMLNHL YFYIMPVFNV DGYHFSWTND
    260 270 280 290 300
    RFWRKTRSRN SRFRCRGVDA NRNWKVKWCD EGASMHPCDD TYCGPFPESE
    310 320 330 340 350
    PEVKAVANFL RKHRKHIRAY LSFHAYAQML LYPYSYKYAT IPNFRCVESA
    360 370 380 390 400
    AYKAVNALQS VYGVRYRYGP ASTTLYVSSG SSMDWAYKNG IPYAFAFELR
    410 420 430
    DTGYFGFLLP EMLIKPTCTE TMLAVKNITM HLLKKCP
    Length:437
    Mass (Da):51,008
    Last modified:January 24, 2006 - v2
    Checksum:i9C21780D4B7D0A98
    GO
    Isoform 2 (identifier: Q8N4T0-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         280-437: DEGASMHPCD...ITMHLLKKCP → GKFGTNWDPD...SHGRLMFFCM

    Note: No experimental confirmation available.
    Show »
    Length:315
    Mass (Da):37,070
    Checksum:iECAA4B2F7F822684
    GO
    Isoform 3 (identifier: Q8N4T0-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-148: Missing.
         281-376: Missing.

    Show »
    Length:193
    Mass (Da):22,889
    Checksum:i3E8C11586C557024
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti45 – 451F → L.
    Corresponds to variant rs10957393 [ dbSNP | Ensembl ].
    VAR_024241
    Natural varianti173 – 1731S → C.2 Publications
    Corresponds to variant rs17853192 [ dbSNP | Ensembl ].
    VAR_025003
    Natural varianti249 – 2491N → S.
    Corresponds to variant rs17343819 [ dbSNP | Ensembl ].
    VAR_048597
    Natural varianti267 – 2671G → R in ETL5; affects protein secretion presumably by altering protein folding or stability. 1 Publication
    VAR_066946
    Natural varianti270 – 2701A → V in FEB11; affects protein secretion presumably by altering protein folding or stability. 1 Publication
    Corresponds to variant rs114402678 [ dbSNP | Ensembl ].
    VAR_066947

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 148148Missing in isoform 3. 1 PublicationVSP_017079Add
    BLAST
    Alternative sequencei280 – 437158DEGAS…LKKCP → GKFGTNWDPDPKVSAGFTLQ NMSPEDSHGRLMFFCM in isoform 2. 1 PublicationVSP_008808Add
    BLAST
    Alternative sequencei281 – 37696Missing in isoform 3. 1 PublicationVSP_017080Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF466284 Genomic DNA. Translation: AAM19307.1.
    BK000188 mRNA. Translation: DAA00037.1.
    AY044833 mRNA. Translation: AAK84941.1.
    AF221594 mRNA. Translation: AAF91231.1.
    BC033684 mRNA. Translation: AAH33684.1.
    CCDSiCCDS6200.1. [Q8N4T0-1]
    RefSeqiNP_065094.3. NM_020361.4. [Q8N4T0-1]
    UniGeneiHs.658850.

    Genome annotation databases

    EnsembliENST00000297770; ENSP00000297770; ENSG00000165078.
    ENST00000518549; ENSP00000431112; ENSG00000165078. [Q8N4T0-2]
    GeneIDi57094.
    KEGGihsa:57094.
    UCSCiuc003xxq.4. human. [Q8N4T0-1]
    uc003xxr.4. human. [Q8N4T0-3]
    uc003xxs.2. human. [Q8N4T0-2]

    Keywords - Coding sequence diversityi

    Alternative splicing, Chromosomal rearrangement, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF466284 Genomic DNA. Translation: AAM19307.1.
    BK000188 mRNA. Translation: DAA00037.1.
    AY044833 mRNA. Translation: AAK84941.1.
    AF221594 mRNA. Translation: AAF91231.1.
    BC033684 mRNA. Translation: AAH33684.1.
    CCDSiCCDS6200.1. [Q8N4T0-1]
    RefSeqiNP_065094.3. NM_020361.4. [Q8N4T0-1]
    UniGeneiHs.658850.

    3D structure databases

    ProteinModelPortaliQ8N4T0.
    SMRiQ8N4T0. Positions 37-433.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi121362. 18 interactions.
    STRINGi9606.ENSP00000297770.

    Protein family/group databases

    MEROPSiM14.018.

    PTM databases

    PhosphoSiteiQ8N4T0.

    Polymorphism and mutation databases

    BioMutaiCPA6.
    DMDMi85683250.

    Proteomic databases

    PaxDbiQ8N4T0.
    PRIDEiQ8N4T0.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000297770; ENSP00000297770; ENSG00000165078.
    ENST00000518549; ENSP00000431112; ENSG00000165078. [Q8N4T0-2]
    GeneIDi57094.
    KEGGihsa:57094.
    UCSCiuc003xxq.4. human. [Q8N4T0-1]
    uc003xxr.4. human. [Q8N4T0-3]
    uc003xxs.2. human. [Q8N4T0-2]

    Organism-specific databases

    CTDi57094.
    GeneCardsiGC08M068384.
    H-InvDBHIX0007565.
    HGNCiHGNC:17245. CPA6.
    MIMi609562. gene.
    614417. phenotype.
    614418. phenotype.
    neXtProtiNX_Q8N4T0.
    Orphaneti165805. Familial mesial temporal lobe epilepsy with febrile seizures.
    PharmGKBiPA38444.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiCOG2866.
    GeneTreeiENSGT00760000119103.
    HOGENOMiHOG000252968.
    HOVERGENiHBG050815.
    InParanoidiQ8N4T0.
    KOiK08782.
    OMAiQLYFYIM.
    PhylomeDBiQ8N4T0.
    TreeFamiTF317197.

    Miscellaneous databases

    GeneWikiiCarboxypeptidase_A6.
    GenomeRNAii57094.
    NextBioi62909.
    PROiQ8N4T0.
    SOURCEiSearch...

    Gene expression databases

    BgeeiQ8N4T0.
    CleanExiHS_CPA6.
    ExpressionAtlasiQ8N4T0. baseline and differential.
    GenevisibleiQ8N4T0. HS.

    Family and domain databases

    Gene3Di3.30.70.340. 1 hit.
    InterProiIPR000834. Peptidase_M14.
    IPR003146. Prot_inh_M14A.
    IPR009020. Prot_inh_propept.
    [Graphical view]
    PfamiPF00246. Peptidase_M14. 1 hit.
    PF02244. Propep_M14. 1 hit.
    [Graphical view]
    PRINTSiPR00765. CRBOXYPTASEA.
    SMARTiSM00631. Zn_pept. 1 hit.
    [Graphical view]
    SUPFAMiSSF54897. SSF54897. 1 hit.
    PROSITEiPS00133. CARBOXYPEPT_ZN_2. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Publicationsi

    « Hide 'large scale' publications
    1. "Identification and characterization of three members of the human metallocarboxypeptidase gene family."
      Wei S., Segura S., Vendrell J., Aviles F.X., Lanoue E., Day R., Feng Y., Fricker L.D.
      J. Biol. Chem. 277:14954-14964(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
    2. "A peptidase gene in chromosome 8q is disrupted by a balanced translocation in a duane syndrome patient."
      Pizzuti A., Calabrese G., Bozzali M., Telvi L., Morizio E., Guida V., Gatta V., Stuppia L., Ion A., Palka G., Dallapiccola B.
      Invest. Ophthalmol. Vis. Sci. 43:3609-3612(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), CHROMOSOMAL TRANSLOCATION.
      Tissue: Retina.
    3. "Novel genes expressed in hematopoietic stem/progenitor cells from myelodysplastic syndrome patients."
      Gu J., Huang Q., Yu Y., Xu S., Han Z., Fu G., Chen Z.
      Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), VARIANT CYS-173.
      Tissue: Hematopoietic stem cell.
    4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT CYS-173.
      Tissue: Brain.
    5. "Characterization of carboxypeptidase A6, an extracellular matrix peptidase."
      Lyons P.J., Callaway M.B., Fricker L.D.
      J. Biol. Chem. 283:7054-7063(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, SUBSTRATE SPECIFICITY.
    6. "Substrate specificity of human carboxypeptidase A6."
      Lyons P.J., Fricker L.D.
      J. Biol. Chem. 285:38234-38242(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, BIOPHYSICOCHEMICAL PROPERTIES.
    7. "Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy."
      Salzmann A., Guipponi M., Lyons P.J., Fricker L.D., Sapio M., Lambercy C., Buresi C., Bencheikh B.O., Lahjouji F., Ouazzani R., Crespel A., Chaigne D., Malafosse A.
      Hum. Mutat. 33:124-135(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY, VARIANT ETL5 ARG-267, VARIANT FEB11 VAL-270, CHARACTERIZATION OF VARIANT ETL5 ARG-267, CHARACTERIZATION OF VARIANT FEB11 VAL-270.

    Entry informationi

    Entry nameiCBPA6_HUMAN
    AccessioniPrimary (citable) accession number: Q8N4T0
    Secondary accession number(s): Q8NEX8, Q8TDE8, Q9NRI9
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 7, 2003
    Last sequence update: January 24, 2006
    Last modified: July 22, 2015
    This is version 126 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 8
      Human chromosome 8: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. Peptidase families
      Classification of peptidase families and list of entries
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.