ID   CAN8_HUMAN              Reviewed;         703 AA.
AC   A6NHC0; B2RXL2;
DT   02-SEP-2008, integrated into UniProtKB/Swiss-Prot.
DT   10-AUG-2010, sequence version 3.
DT   27-MAR-2024, entry version 122.
DE   RecName: Full=Calpain-8;
DE            EC=3.4.22.53;
DE   AltName: Full=New calpain 2;
DE            Short=nCL-2;
DE   AltName: Full=Stomach-specific M-type calpain;
GN   Name=CAPN8; Synonyms=NCL2;
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].
RC   TISSUE=Leukocyte;
RX   PubMed=11523006; DOI=10.1007/s002390010209;
RA   Hata S., Nishi K., Kawamoto T., Lee H.-J., Kawahara H., Maeda T.,
RA   Shintani Y., Sorimachi H., Suzuki K.;
RT   "Both the conserved and the unique gene structure of stomach-specific
RT   calpains reveal processes of calpain gene evolution.";
RL   J. Mol. Evol. 53:191-203(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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).
CC   -!- FUNCTION: Calcium-regulated non-lysosomal thiol-protease. Involved in
CC       membrane trafficking in the gastric surface mucus cells (pit cells) and
CC       may involve the membrane trafficking of mucus cells via interactions
CC       with coat protein. Proteolytically cleaves the beta-subunit of coatomer
CC       complex (By similarity). {ECO:0000250}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Broad endopeptidase specificity.; EC=3.4.22.53;
CC   -!- COFACTOR:
CC       Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000305};
CC       Note=Binds 2 calcium ions. {ECO:0000305};
CC   -!- SUBUNIT: Monomer and homooligomer. Interacts with COPS1/GPS1, COPB1,
CC       EYA2, NME2, NME4 and TOMM70 (By similarity). {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Golgi apparatus
CC       {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Stomach.
CC   -!- DOMAIN: The domain III mediates oligomerization. {ECO:0000250}.
CC   -!- PTM: Undergoes autolytic cleavage between Ala-5 and Ala-6 which gives
CC       rise to fragments extending from Ala-6 to the C-terminus, Ala-6 to the
CC       EF-hand 2 domain and from Ala-6 to the beginning of domain III.
CC       {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the peptidase C2 family. {ECO:0000305}.
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DR   EMBL; AC099065; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CR628412; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CR848842; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC157893; AAI57894.1; -; mRNA.
DR   CCDS; CCDS73038.1; -.
DR   RefSeq; NP_001137434.1; NM_001143962.1.
DR   PDB; 2NQA; X-ray; 2.20 A; A/B=23-346.
DR   PDBsum; 2NQA; -.
DR   AlphaFoldDB; A6NHC0; -.
DR   SMR; A6NHC0; -.
DR   BioGRID; 132835; 9.
DR   IntAct; A6NHC0; 4.
DR   STRING; 9606.ENSP00000355837; -.
DR   MEROPS; C02.007; -.
DR   iPTMnet; A6NHC0; -.
DR   PhosphoSitePlus; A6NHC0; -.
DR   BioMuta; CAPN8; -.
DR   jPOST; A6NHC0; -.
DR   MassIVE; A6NHC0; -.
DR   MaxQB; A6NHC0; -.
DR   PaxDb; 9606-ENSP00000355837; -.
DR   PeptideAtlas; A6NHC0; -.
DR   ProteomicsDB; 1188; -.
DR   Antibodypedia; 61692; 71 antibodies from 16 providers.
DR   DNASU; 388743; -.
DR   Ensembl; ENST00000366872.10; ENSP00000355837.6; ENSG00000203697.12.
DR   GeneID; 388743; -.
DR   KEGG; hsa:388743; -.
DR   MANE-Select; ENST00000366872.10; ENSP00000355837.6; NM_001143962.2; NP_001137434.1.
DR   UCSC; uc031vow.1; human.
DR   AGR; HGNC:1485; -.
DR   CTD; 388743; -.
DR   DisGeNET; 388743; -.
DR   GeneCards; CAPN8; -.
DR   HGNC; HGNC:1485; CAPN8.
DR   HPA; ENSG00000203697; Tissue enriched (stomach).
DR   MIM; 618777; gene.
DR   neXtProt; NX_A6NHC0; -.
DR   OpenTargets; ENSG00000203697; -.
DR   VEuPathDB; HostDB:ENSG00000203697; -.
DR   eggNOG; KOG0045; Eukaryota.
DR   GeneTree; ENSGT00940000160090; -.
DR   HOGENOM; CLU_010982_0_1_1; -.
DR   InParanoid; A6NHC0; -.
DR   OMA; QQWMCLA; -.
DR   OrthoDB; 142935at2759; -.
DR   PhylomeDB; A6NHC0; -.
DR   TreeFam; TF314748; -.
DR   BRENDA; 3.4.22.B28; 2681.
DR   PathwayCommons; A6NHC0; -.
DR   Reactome; R-HSA-1474228; Degradation of the extracellular matrix.
DR   SignaLink; A6NHC0; -.
DR   BioGRID-ORCS; 388743; 12 hits in 327 CRISPR screens.
DR   ChiTaRS; CAPN8; human.
DR   GenomeRNAi; 388743; -.
DR   Pharos; A6NHC0; Tbio.
DR   PRO; PR:A6NHC0; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; A6NHC0; Protein.
DR   Bgee; ENSG00000203697; Expressed in mucosa of transverse colon and 124 other cell types or tissues.
DR   ExpressionAtlas; A6NHC0; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR   GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR   GO; GO:0004198; F:calcium-dependent cysteine-type endopeptidase activity; IBA:GO_Central.
DR   GO; GO:0006508; P:proteolysis; IBA:GO_Central.
DR   CDD; cd00214; Calpain_III; 1.
DR   CDD; cd00044; CysPc; 1.
DR   CDD; cd16191; EFh_PEF_CAPN8; 1.
DR   Gene3D; 2.60.120.380; -; 1.
DR   Gene3D; 3.90.70.10; Cysteine proteinases; 1.
DR   Gene3D; 1.10.238.10; EF-hand; 1.
DR   InterPro; IPR033883; C2_III.
DR   InterPro; IPR022684; Calpain_cysteine_protease.
DR   InterPro; IPR022682; Calpain_domain_III.
DR   InterPro; IPR022683; Calpain_III.
DR   InterPro; IPR036213; Calpain_III_sf.
DR   InterPro; IPR011992; EF-hand-dom_pair.
DR   InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR   InterPro; IPR002048; EF_hand_dom.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   InterPro; IPR000169; Pept_cys_AS.
DR   InterPro; IPR001300; Peptidase_C2_calpain_cat.
DR   PANTHER; PTHR10183; CALPAIN; 1.
DR   PANTHER; PTHR10183:SF374; CALPAIN-8; 1.
DR   Pfam; PF01067; Calpain_III; 1.
DR   Pfam; PF00648; Peptidase_C2; 1.
DR   PRINTS; PR00704; CALPAIN.
DR   SMART; SM00720; calpain_III; 1.
DR   SMART; SM00230; CysPc; 1.
DR   SUPFAM; SSF49758; Calpain large subunit, middle domain (domain III); 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   SUPFAM; SSF47473; EF-hand; 1.
DR   PROSITE; PS50203; CALPAIN_CAT; 1.
DR   PROSITE; PS00018; EF_HAND_1; 2.
DR   PROSITE; PS50222; EF_HAND_2; 3.
DR   PROSITE; PS00139; THIOL_PROTEASE_CYS; 1.
DR   Genevisible; A6NHC0; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Autocatalytic cleavage; Calcium; Cytoplasm; Golgi apparatus;
KW   Hydrolase; Metal-binding; Protease; Reference proteome; Repeat;
KW   Thiol protease.
FT   CHAIN           1..703
FT                   /note="Calpain-8"
FT                   /id="PRO_0000349280"
FT   DOMAIN          45..344
FT                   /note="Calpain catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00239"
FT   DOMAIN          575..610
FT                   /note="EF-hand 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   DOMAIN          618..640
FT                   /note="EF-hand 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   DOMAIN          670..703
FT                   /note="EF-hand 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   REGION          356..379
FT                   /note="Domain III"
FT   ACT_SITE        105
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        262
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        286
FT                   /evidence="ECO:0000250"
FT   BINDING         588
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         590
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         592
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         594
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         599
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         618
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         620
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         622
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         624
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         629
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   CONFLICT        245
FT                   /note="S -> Y (in Ref. 3; AAI57894)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        592
FT                   /note="T -> M (in Ref. 3; AAI57894)"
FT                   /evidence="ECO:0000305"
FT   HELIX           27..29
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           32..42
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           55..58
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   TURN            69..72
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          74..76
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           78..81
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           94..96
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           105..114
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           118..124
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          136..145
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          148..155
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          158..161
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          164..167
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           177..188
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          190..192
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           193..195
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           207..209
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          213..216
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           224..234
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          237..241
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           247..249
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          259..261
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          264..274
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          277..285
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           302..306
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           309..315
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          321..327
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   HELIX           328..334
FT                   /evidence="ECO:0007829|PDB:2NQA"
FT   STRAND          337..341
FT                   /evidence="ECO:0007829|PDB:2NQA"
SQ   SEQUENCE   703 AA;  79144 MW;  2A6DFFC0814894A8 CRC64;
     MAAQAAGVSR QRAATQGLGS NQNALKYLGQ DFKTLRQQCL DSGVLFKDPE FPACPSALGY
     KDLGPGSPQT QGIIWKRPTE LCPSPQFIVG GATRTDICQG GLGDCWLLAA IASLTLNEEL
     LYRVVPRDQD FQENYAGIFH FQFWQYGEWV EVVIDDRLPT KNGQLLFLHS EQGNEFWSAL
     LEKAYAKLNG CYEALAGGST VEGFEDFTGG ISEFYDLKKP PANLYQIIRK ALCAGSLLGC
     SIDVSSAAEA EAITSQKLVK SHAYSVTGVE EVNFQGHPEK LIRLRNPWGE VEWSGAWSDD
     APEWNHIDPR RKEELDKKVE DGEFWMSLSD FVRQFSRLEI CNLSPDSLSS EEVHKWNLVL
     FNGHWTRGST AGGCQNYPAT YWTNPQFKIR LDEVDEDQEE SIGEPCCTVL LGLMQKNRRW
     RKRIGQGMLS IGYAVYQVPK ELESHTDAHL GRDFFLAYQP SARTSTYVNL REVSGRARLP
     PGEYLVVPST FEPFKDGEFC LRVFSEKKAQ ALEIGDVVAG NPYEPHPSEV DQEDDQFRRL
     FEKLAGKDSE ITANALKILL NEAFSKRTDI KFDGFNINTC REMISLLDSN GTGTLGAVEF
     KTLWLKIQKY LEIYWETDYN HSGTIDAHEM RTALRKAGFT LNSQVQQTIA LRYACSKLGI
     NFDSFVACMI RLETLFKLFS LLDEDKDGMV QLSLAEWLCC VLV
//