Full text data of CAST
CAST
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Calpastatin (Calpain inhibitor; Sperm BS-17 component)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Calpastatin (Calpain inhibitor; Sperm BS-17 component)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00396082
IPI00396082 Similar to Calpain inhibitor calpain inhibitor activity soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00396082 Similar to Calpain inhibitor calpain inhibitor activity soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P20810
ID ICAL_HUMAN Reviewed; 708 AA.
AC P20810; G5E946; G5E9D3; O95360; Q05DE8; Q7Z4K0; Q96D08; Q9H1Z5;
read moreDT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 4.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=Calpastatin;
DE AltName: Full=Calpain inhibitor;
DE AltName: Full=Sperm BS-17 component;
GN Name=CAST;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS SER-408 AND
RP GLY-592.
RX PubMed=2577276;
RA Asada K., Ishino Y., Shimada M., Shimojo T., Endo M., Kimizuka F.,
RA Kato I., Maki M., Hatanaka M., Murachi T.;
RT "cDNA cloning of human calpastatin: sequence homology among human,
RT pig, and rabbit calpastatins.";
RL J. Enzym. Inhib. 3:49-56(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Testis;
RX PubMed=11978196;
RA Zhu H., Zhou Z.-M., Li J.-M., Zhu H., Cheng L.-J., Shan Y.-X.,
RA Yin L.-L., Sha J.H.;
RT "Cloning and characterization of a novel isoform of calpastatin in
RT human adult testis.";
RL Acta Pharmacol. Sin. 23:450-454(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND ALTERNATIVE
RP SPLICING (ISOFORMS 6 AND 7).
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 1-319 (ISOFORM 5).
RC TISSUE=Lung, and Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-479 (ISOFORM 8), AND
RP VARIANT SER-408.
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-283 (ISOFORM 1), AND ALTERNATIVE
RP SPLICING.
RC TISSUE=Lung;
RX PubMed=1569094;
RA Lee W.J., Ma H., Takano E., Yang H.Q., Hatanaka M., Maki M.;
RT "Molecular diversity in amino-terminal domains of human calpastatin by
RT exon skipping.";
RL J. Biol. Chem. 267:8437-8442(1992).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 101-317.
RX PubMed=2553724;
RA Maki M., Bagci H., Hamaguchi K., Ueda M., Murachi T., Hatanaka M.;
RT "Inhibition of calpain by a synthetic oligopeptide corresponding to an
RT exon of the human calpastatin gene.";
RL J. Biol. Chem. 264:18866-18869(1989).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 125-283 (ISOFORMS 2/3).
RX PubMed=2407243; DOI=10.1016/0006-291X(90)91035-Q;
RA Uemori T., Shimojo T., Asada K., Asano T., Kimizuka F., Kato I.,
RA Maki M., Hatanaka M., Murachi T., Hanzawa H., Arata Y.;
RT "Characterization of a functional domain of human calpastatin.";
RL Biochem. Biophys. Res. Commun. 166:1485-1493(1990).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 153-708 (ISOFORMS 2/3), SEQUENCE
RP REVISION, AND VARIANT SER-408.
RA Wang L.F.;
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 523-708 (ISOFORMS 1/2/3/4).
RC TISSUE=Testis;
RX PubMed=7951045;
RA Wang L.F., Wei S.G., Miao S.Y., Liu Q.Y., Koide S.S.;
RT "Calpastatin gene in human testis.";
RL Biochem. Mol. Biol. Int. 33:245-252(1994).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 425-708 (ISOFORMS 1/2/3/4).
RC TISSUE=Placenta;
RX PubMed=7706496; DOI=10.1172/JCI117870;
RA Despres N., Talbot G., Plouffe B., Boire G., Menard H.A.;
RT "Detection and expression of a cDNA clone that encodes a polypeptide
RT containing two inhibitory domains of human calpastatin and its
RT recognition by rheumatoid arthritis sera.";
RL J. Clin. Invest. 95:1891-1896(1995).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 244-708 (ISOFORMS 1/2/3/4), AND VARIANT
RP SER-408.
RC TISSUE=Placenta;
RA El-Amine M., Talbot G., Despres N., Asselin C., Boire G., Menard H.A.;
RL Submitted (JUL-1995) to the EMBL/GenBank/DDBJ databases.
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 636-708 (ISOFORMS 1/2/3/4).
RA Rochdi M.D., El-Amine M., Menard H.A.;
RT "New calpastatin 3' UTR.";
RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases.
RN [16]
RP PHOSPHORYLATION.
RX PubMed=1995645;
RA Adachi Y., Ishida-Takahashi A., Takahashi C., Takano E., Murachi T.,
RA Hatanaka M.;
RT "Phosphorylation and subcellular distribution of calpastatin in human
RT hematopoietic system cells.";
RL J. Biol. Chem. 266:3968-3972(1991).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-243; SER-364; SER-366
RP AND SER-373, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-133; SER-575 AND
RP SER-577, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-11 (ISOFORMS 5;
RP 6; 7 AND 9), AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
CC -!- FUNCTION: Specific inhibition of calpain (calcium-dependent
CC cysteine protease). Plays a key role in postmortem tenderization
CC of meat and have been proposed to be involved in muscle protein
CC degradation in living tissue.
CC -!- INTERACTION:
CC P16333:NCK1; NbExp=2; IntAct=EBI-1268770, EBI-389883;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=9;
CC Comment=Additional isoforms seem to exist;
CC Name=1;
CC IsoId=P20810-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P20810-2; Sequence=VSP_000744;
CC Name=3;
CC IsoId=P20810-3; Sequence=VSP_000741, VSP_000744;
CC Name=4;
CC IsoId=P20810-4; Sequence=VSP_000742, VSP_000743;
CC Name=5;
CC IsoId=P20810-5; Sequence=VSP_038037, VSP_000744;
CC Note=Contains a phosphoserine at position 11;
CC Name=6;
CC IsoId=P20810-6; Sequence=VSP_038038;
CC Note=Contains a phosphoserine at position 11;
CC Name=7;
CC IsoId=P20810-7; Sequence=VSP_038038, VSP_000743;
CC Note=Contains a phosphoserine at position 11;
CC Name=8;
CC IsoId=P20810-8; Sequence=VSP_000742;
CC Note=No experimental confirmation available;
CC Name=9;
CC IsoId=P20810-9; Sequence=VSP_047393;
CC Note=Gene prediction based on EST data. Contains a phosphoserine
CC at position 11;
CC -!- DOMAIN: Each of the four flexible inhibitory domains can inhibit
CC one calcium-bound calpain molecule by occupying both sides of the
CC active site (By similarity).
CC -!- PTM: The N-terminus is blocked.
CC -!- SIMILARITY: Belongs to the protease inhibitor I27 (calpastatin)
CC family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH16066.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence;
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DR EMBL; D16217; BAA03747.1; -; mRNA.
DR EMBL; D50827; BAA09438.1; -; mRNA.
DR EMBL; AF327443; AAG48151.1; -; mRNA.
DR EMBL; BT009783; AAP88785.1; -; mRNA.
DR EMBL; AC008906; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC020900; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104125; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471084; EAW96068.1; -; Genomic_DNA.
DR EMBL; CH471084; EAW96071.1; -; Genomic_DNA.
DR EMBL; CH471084; EAW96075.1; -; Genomic_DNA.
DR EMBL; BC013579; AAH13579.1; -; mRNA.
DR EMBL; BC016066; AAH16066.1; ALT_SEQ; mRNA.
DR EMBL; AL832349; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; M86258; AAB59398.1; -; mRNA.
DR EMBL; M28230; AAA52066.1; -; Genomic_DNA.
DR EMBL; M28227; AAA52066.1; JOINED; Genomic_DNA.
DR EMBL; M28228; AAA52066.1; JOINED; Genomic_DNA.
DR EMBL; M28229; AAA52066.1; JOINED; Genomic_DNA.
DR EMBL; M33328; AAA52296.1; -; mRNA.
DR EMBL; U26724; AAC50136.2; -; mRNA.
DR EMBL; S73329; AAB32311.1; -; mRNA.
DR EMBL; U38525; AAA80684.1; -; mRNA.
DR EMBL; U31345; AAB60371.1; -; mRNA.
DR EMBL; U31346; AAB60372.1; -; mRNA.
DR EMBL; AF095891; AAD09102.1; -; mRNA.
DR PIR; A38091; A38091.
DR RefSeq; NP_001035905.1; NM_001042440.3.
DR RefSeq; NP_001177371.1; NM_001190442.1.
DR RefSeq; NP_001271141.1; NM_001284212.1.
DR RefSeq; NP_775083.1; NM_173060.3.
DR UniGene; Hs.436186; -.
DR DisProt; DP00196; -.
DR ProteinModelPortal; P20810; -.
DR SMR; P20810; 156-240, 566-659.
DR IntAct; P20810; 9.
DR STRING; 9606.ENSP00000379158; -.
DR MEROPS; I27.001; -.
DR PhosphoSite; P20810; -.
DR DMDM; 126302556; -.
DR PaxDb; P20810; -.
DR PRIDE; P20810; -.
DR DNASU; 831; -.
DR Ensembl; ENST00000309190; ENSP00000312523; ENSG00000153113.
DR Ensembl; ENST00000325674; ENSP00000320319; ENSG00000153113.
DR Ensembl; ENST00000338252; ENSP00000343421; ENSG00000153113.
DR Ensembl; ENST00000341926; ENSP00000339914; ENSG00000153113.
DR Ensembl; ENST00000359176; ENSP00000352098; ENSG00000153113.
DR Ensembl; ENST00000395812; ENSP00000379157; ENSG00000153113.
DR Ensembl; ENST00000395813; ENSP00000379158; ENSG00000153113.
DR Ensembl; ENST00000508830; ENSP00000425721; ENSG00000153113.
DR Ensembl; ENST00000510098; ENSP00000427195; ENSG00000153113.
DR GeneID; 831; -.
DR KEGG; hsa:831; -.
DR UCSC; uc003klz.1; human.
DR CTD; 831; -.
DR GeneCards; GC05P095865; -.
DR HGNC; HGNC:1515; CAST.
DR HPA; CAB009491; -.
DR MIM; 114090; gene.
DR neXtProt; NX_P20810; -.
DR PharmGKB; PA26098; -.
DR eggNOG; NOG25116; -.
DR HOGENOM; HOG000082405; -.
DR HOVERGEN; HBG000183; -.
DR InParanoid; P20810; -.
DR KO; K04281; -.
DR OMA; KSSSMNP; -.
DR OrthoDB; EOG77HDF0; -.
DR ChiTaRS; CAST; human.
DR GeneWiki; Calpastatin; -.
DR GenomeRNAi; 831; -.
DR NextBio; 3422; -.
DR PRO; PR:P20810; -.
DR ArrayExpress; P20810; -.
DR Bgee; P20810; -.
DR CleanEx; HS_CAST; -.
DR Genevestigator; P20810; -.
DR GO; GO:0016020; C:membrane; IEA:Ensembl.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc.
DR GO; GO:2000675; P:negative regulation of type B pancreatic cell apoptotic process; IDA:BHF-UCL.
DR InterPro; IPR026998; Calpastatin.
DR InterPro; IPR001259; Prot_inh_calpain.
DR PANTHER; PTHR10077; PTHR10077; 1.
DR Pfam; PF00748; Calpain_inhib; 4.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Phosphoprotein; Polymorphism;
KW Protease inhibitor; Reference proteome; Repeat;
KW Thiol protease inhibitor.
FT CHAIN 1 708 Calpastatin.
FT /FTId=PRO_0000147632.
FT REPEAT 170 222 Inhibitory domain 1.
FT REPEAT 304 356 Inhibitory domain 2.
FT REPEAT 446 499 Inhibitory domain 3.
FT REPEAT 583 636 Inhibitory domain 4.
FT MOD_RES 133 133 Phosphoserine.
FT MOD_RES 243 243 Phosphoserine.
FT MOD_RES 364 364 Phosphoserine.
FT MOD_RES 366 366 Phosphoserine.
FT MOD_RES 373 373 Phosphoserine.
FT MOD_RES 575 575 Phosphoserine.
FT MOD_RES 577 577 Phosphoserine.
FT VAR_SEQ 1 105 Missing (in isoform 3).
FT /FTId=VSP_000741.
FT VAR_SEQ 1 62 MNPTETKAIPVSQQMEGPHLPNKKKHKKQAVKTEPEKKSQS
FT TKLSVVHEKKSQEGKPKEHTE -> MSQPGQKPAASPRPRR
FT AAAARRTHEHVSEKTSESPSKPGEKKGSDEKKAASLGSSQS
FT SRTYAGGTASATKVSASSGATSKSSSMNPTETKAVKTEPEK
FT KSQSTK (in isoform 9).
FT /FTId=VSP_047393.
FT VAR_SEQ 1 29 MNPTETKAIPVSQQMEGPHLPNKKKHKKQ -> MSQPGQKP
FT AASPRPRRAAAARRTHEHVSEKTSESPSKPGEKKGSDEKKA
FT ASLGSSQSSRTYAGGTASATKVSASSGATSKSSSMNPTETK
FT (in isoform 5).
FT /FTId=VSP_038037.
FT VAR_SEQ 1 1 M -> MSQPGQKPAASPRPRRAAAARRTHEHVSEKTSESPS
FT KPGEKKGSDEKKAASLGSSQSSRTYAGGTASATKVSASSGA
FT TSKSSSM (in isoform 6 and isoform 7).
FT /FTId=VSP_038038.
FT VAR_SEQ 9 30 Missing (in isoform 4 and isoform 8).
FT /FTId=VSP_000742.
FT VAR_SEQ 44 62 Missing (in isoform 4 and isoform 7).
FT /FTId=VSP_000743.
FT VAR_SEQ 212 224 Missing (in isoform 2, isoform 3 and
FT isoform 5).
FT /FTId=VSP_000744.
FT VARIANT 380 380 E -> K (in dbSNP:rs1643702).
FT /FTId=VAR_030741.
FT VARIANT 408 408 C -> S (in dbSNP:rs754615).
FT /FTId=VAR_022686.
FT VARIANT 537 537 A -> V (in dbSNP:rs4948).
FT /FTId=VAR_030742.
FT VARIANT 592 592 E -> G.
FT /FTId=VAR_005298.
FT CONFLICT 467 467 R -> L (in Ref. 11; AAC50136).
FT CONFLICT 486 488 VKD -> GKE (in Ref. 11; AAC50136).
FT CONFLICT 543 543 V -> L (in Ref. 11; AAC50136).
FT CONFLICT 562 562 Missing (in Ref. 14; AAB60371).
FT CONFLICT 651 651 I -> V (in Ref. 15; AAD09102).
SQ SEQUENCE 708 AA; 76573 MW; 2DB0C14B860E89C7 CRC64;
MNPTETKAIP VSQQMEGPHL PNKKKHKKQA VKTEPEKKSQ STKLSVVHEK KSQEGKPKEH
TEPKSLPKQA SDTGSNDAHN KKAVSRSAEQ QPSEKSTEPK TKPQDMISAG GESVAGITAI
SGKPGDKKKE KKSLTPAVPV ESKPDKPSGK SGMDAALDDL IDTLGGPEET EEENTTYTGP
EVSDPMSSTY IEELGKREVT IPPKYRELLA KKEGITGPPA DSSKPIGPDD AIDALSSDFT
CGSPTAAGKK TEKEESTEVL KAQSAGTVRS AAPPQEKKRK VEKDTMSDQA LEALSASLGT
RQAEPELDLR SIKEVDEAKA KEEKLEKCGE DDETIPSEYR LKPATDKDGK PLLPEPEEKP
KPRSESELID ELSEDFDRSE CKEKPSKPTE KTEESKAAAP APVSEAVCRT SMCSIQSAPP
EPATLKGTVP DDAVEALADS LGKKEADPED GKPVMDKVKE KAKEEDREKL GEKEETIPPD
YRLEEVKDKD GKPLLPKESK EQLPPMSEDF LLDALSEDFS GPQNASSLKF EDAKLAAAIS
EVVSQTPAST TQAGAPPRDT SQSDKDLDDA LDKLSDSLGQ RQPDPDENKP MEDKVKEKAK
AEHRDKLGER DDTIPPEYRH LLDDNGQDKP VKPPTKKSED SKKPADDQDP IDALSGDLDS
CPSTTETSQN TAKDKCKKAA SSSKAPKNGG KAKDSAKTTE ETSKPKDD
//
ID ICAL_HUMAN Reviewed; 708 AA.
AC P20810; G5E946; G5E9D3; O95360; Q05DE8; Q7Z4K0; Q96D08; Q9H1Z5;
read moreDT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 20-FEB-2007, sequence version 4.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=Calpastatin;
DE AltName: Full=Calpain inhibitor;
DE AltName: Full=Sperm BS-17 component;
GN Name=CAST;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS SER-408 AND
RP GLY-592.
RX PubMed=2577276;
RA Asada K., Ishino Y., Shimada M., Shimojo T., Endo M., Kimizuka F.,
RA Kato I., Maki M., Hatanaka M., Murachi T.;
RT "cDNA cloning of human calpastatin: sequence homology among human,
RT pig, and rabbit calpastatins.";
RL J. Enzym. Inhib. 3:49-56(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Testis;
RX PubMed=11978196;
RA Zhu H., Zhou Z.-M., Li J.-M., Zhu H., Cheng L.-J., Shan Y.-X.,
RA Yin L.-L., Sha J.H.;
RT "Cloning and characterization of a novel isoform of calpastatin in
RT human adult testis.";
RL Acta Pharmacol. Sin. 23:450-454(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND ALTERNATIVE
RP SPLICING (ISOFORMS 6 AND 7).
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 1-319 (ISOFORM 5).
RC TISSUE=Lung, and Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-479 (ISOFORM 8), AND
RP VARIANT SER-408.
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-283 (ISOFORM 1), AND ALTERNATIVE
RP SPLICING.
RC TISSUE=Lung;
RX PubMed=1569094;
RA Lee W.J., Ma H., Takano E., Yang H.Q., Hatanaka M., Maki M.;
RT "Molecular diversity in amino-terminal domains of human calpastatin by
RT exon skipping.";
RL J. Biol. Chem. 267:8437-8442(1992).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 101-317.
RX PubMed=2553724;
RA Maki M., Bagci H., Hamaguchi K., Ueda M., Murachi T., Hatanaka M.;
RT "Inhibition of calpain by a synthetic oligopeptide corresponding to an
RT exon of the human calpastatin gene.";
RL J. Biol. Chem. 264:18866-18869(1989).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 125-283 (ISOFORMS 2/3).
RX PubMed=2407243; DOI=10.1016/0006-291X(90)91035-Q;
RA Uemori T., Shimojo T., Asada K., Asano T., Kimizuka F., Kato I.,
RA Maki M., Hatanaka M., Murachi T., Hanzawa H., Arata Y.;
RT "Characterization of a functional domain of human calpastatin.";
RL Biochem. Biophys. Res. Commun. 166:1485-1493(1990).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 153-708 (ISOFORMS 2/3), SEQUENCE
RP REVISION, AND VARIANT SER-408.
RA Wang L.F.;
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 523-708 (ISOFORMS 1/2/3/4).
RC TISSUE=Testis;
RX PubMed=7951045;
RA Wang L.F., Wei S.G., Miao S.Y., Liu Q.Y., Koide S.S.;
RT "Calpastatin gene in human testis.";
RL Biochem. Mol. Biol. Int. 33:245-252(1994).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 425-708 (ISOFORMS 1/2/3/4).
RC TISSUE=Placenta;
RX PubMed=7706496; DOI=10.1172/JCI117870;
RA Despres N., Talbot G., Plouffe B., Boire G., Menard H.A.;
RT "Detection and expression of a cDNA clone that encodes a polypeptide
RT containing two inhibitory domains of human calpastatin and its
RT recognition by rheumatoid arthritis sera.";
RL J. Clin. Invest. 95:1891-1896(1995).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 244-708 (ISOFORMS 1/2/3/4), AND VARIANT
RP SER-408.
RC TISSUE=Placenta;
RA El-Amine M., Talbot G., Despres N., Asselin C., Boire G., Menard H.A.;
RL Submitted (JUL-1995) to the EMBL/GenBank/DDBJ databases.
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 636-708 (ISOFORMS 1/2/3/4).
RA Rochdi M.D., El-Amine M., Menard H.A.;
RT "New calpastatin 3' UTR.";
RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases.
RN [16]
RP PHOSPHORYLATION.
RX PubMed=1995645;
RA Adachi Y., Ishida-Takahashi A., Takahashi C., Takano E., Murachi T.,
RA Hatanaka M.;
RT "Phosphorylation and subcellular distribution of calpastatin in human
RT hematopoietic system cells.";
RL J. Biol. Chem. 266:3968-3972(1991).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-243; SER-364; SER-366
RP AND SER-373, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-133; SER-575 AND
RP SER-577, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-11 (ISOFORMS 5;
RP 6; 7 AND 9), AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
CC -!- FUNCTION: Specific inhibition of calpain (calcium-dependent
CC cysteine protease). Plays a key role in postmortem tenderization
CC of meat and have been proposed to be involved in muscle protein
CC degradation in living tissue.
CC -!- INTERACTION:
CC P16333:NCK1; NbExp=2; IntAct=EBI-1268770, EBI-389883;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=9;
CC Comment=Additional isoforms seem to exist;
CC Name=1;
CC IsoId=P20810-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P20810-2; Sequence=VSP_000744;
CC Name=3;
CC IsoId=P20810-3; Sequence=VSP_000741, VSP_000744;
CC Name=4;
CC IsoId=P20810-4; Sequence=VSP_000742, VSP_000743;
CC Name=5;
CC IsoId=P20810-5; Sequence=VSP_038037, VSP_000744;
CC Note=Contains a phosphoserine at position 11;
CC Name=6;
CC IsoId=P20810-6; Sequence=VSP_038038;
CC Note=Contains a phosphoserine at position 11;
CC Name=7;
CC IsoId=P20810-7; Sequence=VSP_038038, VSP_000743;
CC Note=Contains a phosphoserine at position 11;
CC Name=8;
CC IsoId=P20810-8; Sequence=VSP_000742;
CC Note=No experimental confirmation available;
CC Name=9;
CC IsoId=P20810-9; Sequence=VSP_047393;
CC Note=Gene prediction based on EST data. Contains a phosphoserine
CC at position 11;
CC -!- DOMAIN: Each of the four flexible inhibitory domains can inhibit
CC one calcium-bound calpain molecule by occupying both sides of the
CC active site (By similarity).
CC -!- PTM: The N-terminus is blocked.
CC -!- SIMILARITY: Belongs to the protease inhibitor I27 (calpastatin)
CC family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH16066.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence;
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DR EMBL; D16217; BAA03747.1; -; mRNA.
DR EMBL; D50827; BAA09438.1; -; mRNA.
DR EMBL; AF327443; AAG48151.1; -; mRNA.
DR EMBL; BT009783; AAP88785.1; -; mRNA.
DR EMBL; AC008906; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC020900; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104125; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471084; EAW96068.1; -; Genomic_DNA.
DR EMBL; CH471084; EAW96071.1; -; Genomic_DNA.
DR EMBL; CH471084; EAW96075.1; -; Genomic_DNA.
DR EMBL; BC013579; AAH13579.1; -; mRNA.
DR EMBL; BC016066; AAH16066.1; ALT_SEQ; mRNA.
DR EMBL; AL832349; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; M86258; AAB59398.1; -; mRNA.
DR EMBL; M28230; AAA52066.1; -; Genomic_DNA.
DR EMBL; M28227; AAA52066.1; JOINED; Genomic_DNA.
DR EMBL; M28228; AAA52066.1; JOINED; Genomic_DNA.
DR EMBL; M28229; AAA52066.1; JOINED; Genomic_DNA.
DR EMBL; M33328; AAA52296.1; -; mRNA.
DR EMBL; U26724; AAC50136.2; -; mRNA.
DR EMBL; S73329; AAB32311.1; -; mRNA.
DR EMBL; U38525; AAA80684.1; -; mRNA.
DR EMBL; U31345; AAB60371.1; -; mRNA.
DR EMBL; U31346; AAB60372.1; -; mRNA.
DR EMBL; AF095891; AAD09102.1; -; mRNA.
DR PIR; A38091; A38091.
DR RefSeq; NP_001035905.1; NM_001042440.3.
DR RefSeq; NP_001177371.1; NM_001190442.1.
DR RefSeq; NP_001271141.1; NM_001284212.1.
DR RefSeq; NP_775083.1; NM_173060.3.
DR UniGene; Hs.436186; -.
DR DisProt; DP00196; -.
DR ProteinModelPortal; P20810; -.
DR SMR; P20810; 156-240, 566-659.
DR IntAct; P20810; 9.
DR STRING; 9606.ENSP00000379158; -.
DR MEROPS; I27.001; -.
DR PhosphoSite; P20810; -.
DR DMDM; 126302556; -.
DR PaxDb; P20810; -.
DR PRIDE; P20810; -.
DR DNASU; 831; -.
DR Ensembl; ENST00000309190; ENSP00000312523; ENSG00000153113.
DR Ensembl; ENST00000325674; ENSP00000320319; ENSG00000153113.
DR Ensembl; ENST00000338252; ENSP00000343421; ENSG00000153113.
DR Ensembl; ENST00000341926; ENSP00000339914; ENSG00000153113.
DR Ensembl; ENST00000359176; ENSP00000352098; ENSG00000153113.
DR Ensembl; ENST00000395812; ENSP00000379157; ENSG00000153113.
DR Ensembl; ENST00000395813; ENSP00000379158; ENSG00000153113.
DR Ensembl; ENST00000508830; ENSP00000425721; ENSG00000153113.
DR Ensembl; ENST00000510098; ENSP00000427195; ENSG00000153113.
DR GeneID; 831; -.
DR KEGG; hsa:831; -.
DR UCSC; uc003klz.1; human.
DR CTD; 831; -.
DR GeneCards; GC05P095865; -.
DR HGNC; HGNC:1515; CAST.
DR HPA; CAB009491; -.
DR MIM; 114090; gene.
DR neXtProt; NX_P20810; -.
DR PharmGKB; PA26098; -.
DR eggNOG; NOG25116; -.
DR HOGENOM; HOG000082405; -.
DR HOVERGEN; HBG000183; -.
DR InParanoid; P20810; -.
DR KO; K04281; -.
DR OMA; KSSSMNP; -.
DR OrthoDB; EOG77HDF0; -.
DR ChiTaRS; CAST; human.
DR GeneWiki; Calpastatin; -.
DR GenomeRNAi; 831; -.
DR NextBio; 3422; -.
DR PRO; PR:P20810; -.
DR ArrayExpress; P20810; -.
DR Bgee; P20810; -.
DR CleanEx; HS_CAST; -.
DR Genevestigator; P20810; -.
DR GO; GO:0016020; C:membrane; IEA:Ensembl.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc.
DR GO; GO:2000675; P:negative regulation of type B pancreatic cell apoptotic process; IDA:BHF-UCL.
DR InterPro; IPR026998; Calpastatin.
DR InterPro; IPR001259; Prot_inh_calpain.
DR PANTHER; PTHR10077; PTHR10077; 1.
DR Pfam; PF00748; Calpain_inhib; 4.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Phosphoprotein; Polymorphism;
KW Protease inhibitor; Reference proteome; Repeat;
KW Thiol protease inhibitor.
FT CHAIN 1 708 Calpastatin.
FT /FTId=PRO_0000147632.
FT REPEAT 170 222 Inhibitory domain 1.
FT REPEAT 304 356 Inhibitory domain 2.
FT REPEAT 446 499 Inhibitory domain 3.
FT REPEAT 583 636 Inhibitory domain 4.
FT MOD_RES 133 133 Phosphoserine.
FT MOD_RES 243 243 Phosphoserine.
FT MOD_RES 364 364 Phosphoserine.
FT MOD_RES 366 366 Phosphoserine.
FT MOD_RES 373 373 Phosphoserine.
FT MOD_RES 575 575 Phosphoserine.
FT MOD_RES 577 577 Phosphoserine.
FT VAR_SEQ 1 105 Missing (in isoform 3).
FT /FTId=VSP_000741.
FT VAR_SEQ 1 62 MNPTETKAIPVSQQMEGPHLPNKKKHKKQAVKTEPEKKSQS
FT TKLSVVHEKKSQEGKPKEHTE -> MSQPGQKPAASPRPRR
FT AAAARRTHEHVSEKTSESPSKPGEKKGSDEKKAASLGSSQS
FT SRTYAGGTASATKVSASSGATSKSSSMNPTETKAVKTEPEK
FT KSQSTK (in isoform 9).
FT /FTId=VSP_047393.
FT VAR_SEQ 1 29 MNPTETKAIPVSQQMEGPHLPNKKKHKKQ -> MSQPGQKP
FT AASPRPRRAAAARRTHEHVSEKTSESPSKPGEKKGSDEKKA
FT ASLGSSQSSRTYAGGTASATKVSASSGATSKSSSMNPTETK
FT (in isoform 5).
FT /FTId=VSP_038037.
FT VAR_SEQ 1 1 M -> MSQPGQKPAASPRPRRAAAARRTHEHVSEKTSESPS
FT KPGEKKGSDEKKAASLGSSQSSRTYAGGTASATKVSASSGA
FT TSKSSSM (in isoform 6 and isoform 7).
FT /FTId=VSP_038038.
FT VAR_SEQ 9 30 Missing (in isoform 4 and isoform 8).
FT /FTId=VSP_000742.
FT VAR_SEQ 44 62 Missing (in isoform 4 and isoform 7).
FT /FTId=VSP_000743.
FT VAR_SEQ 212 224 Missing (in isoform 2, isoform 3 and
FT isoform 5).
FT /FTId=VSP_000744.
FT VARIANT 380 380 E -> K (in dbSNP:rs1643702).
FT /FTId=VAR_030741.
FT VARIANT 408 408 C -> S (in dbSNP:rs754615).
FT /FTId=VAR_022686.
FT VARIANT 537 537 A -> V (in dbSNP:rs4948).
FT /FTId=VAR_030742.
FT VARIANT 592 592 E -> G.
FT /FTId=VAR_005298.
FT CONFLICT 467 467 R -> L (in Ref. 11; AAC50136).
FT CONFLICT 486 488 VKD -> GKE (in Ref. 11; AAC50136).
FT CONFLICT 543 543 V -> L (in Ref. 11; AAC50136).
FT CONFLICT 562 562 Missing (in Ref. 14; AAB60371).
FT CONFLICT 651 651 I -> V (in Ref. 15; AAD09102).
SQ SEQUENCE 708 AA; 76573 MW; 2DB0C14B860E89C7 CRC64;
MNPTETKAIP VSQQMEGPHL PNKKKHKKQA VKTEPEKKSQ STKLSVVHEK KSQEGKPKEH
TEPKSLPKQA SDTGSNDAHN KKAVSRSAEQ QPSEKSTEPK TKPQDMISAG GESVAGITAI
SGKPGDKKKE KKSLTPAVPV ESKPDKPSGK SGMDAALDDL IDTLGGPEET EEENTTYTGP
EVSDPMSSTY IEELGKREVT IPPKYRELLA KKEGITGPPA DSSKPIGPDD AIDALSSDFT
CGSPTAAGKK TEKEESTEVL KAQSAGTVRS AAPPQEKKRK VEKDTMSDQA LEALSASLGT
RQAEPELDLR SIKEVDEAKA KEEKLEKCGE DDETIPSEYR LKPATDKDGK PLLPEPEEKP
KPRSESELID ELSEDFDRSE CKEKPSKPTE KTEESKAAAP APVSEAVCRT SMCSIQSAPP
EPATLKGTVP DDAVEALADS LGKKEADPED GKPVMDKVKE KAKEEDREKL GEKEETIPPD
YRLEEVKDKD GKPLLPKESK EQLPPMSEDF LLDALSEDFS GPQNASSLKF EDAKLAAAIS
EVVSQTPAST TQAGAPPRDT SQSDKDLDDA LDKLSDSLGQ RQPDPDENKP MEDKVKEKAK
AEHRDKLGER DDTIPPEYRH LLDDNGQDKP VKPPTKKSED SKKPADDQDP IDALSGDLDS
CPSTTETSQN TAKDKCKKAA SSSKAPKNGG KAKDSAKTTE ETSKPKDD
//
MIM
114090
*RECORD*
*FIELD* NO
114090
*FIELD* TI
*114090 CALPASTATIN; CAST
*FIELD* TX
DESCRIPTION
Calpastatin is an endogenous inhibitor of calpains (see 114170)
read moreconsisting of 4 inhibitory repeats, each of which neutralizes an
activated calpain. Unlike proteinases, it is an intrinsically
unstructured protein, adopting a defined structure only upon binding to
active calpain ().
GENE FUNCTION
In erythrocytes of patients with essential hypertension (see 145500),
the level of calpastatin activity is significantly lower than in the red
cells of normotensive subjects. Pontremoli et al. (1988) demonstrated by
Western blot analysis that the decreased inhibitor activity is the
result of a decrease in the amount of the inhibitor protein. Calpastatin
isolated and purified from erythrocytes of normotensive and hypertensive
patients had identical specific activities. Pontremoli et al. (1988)
also presented evidence indicating that the decreased level of
calpastatin cannot be ascribed to accelerated decay during the red cell
life span.
Mimori et al. (1995) demonstrated that anti-calpastatin autoantibodies
are present in as many as 57% of rheumatoid arthritis patients and
concluded that they may participate in pathogenic mechanisms of this and
other rheumatic diseases which showed a lower frequency.
MAPPING
Using a cDNA probe encoding the 5-prime terminal region of CAST for
spot-blot analysis of sorted chromosomes and chromosomal in situ
hybridization, Inazawa et al. (1990) assigned the CAST gene to 5q14-q22.
Inazawa et al. (1991) mapped CAST to 5q15-q21 by 2 methods of in situ
hybridization and confirmed the results by spot-blot analysis of sorted
chromosomes.
BIOCHEMICAL FEATURES
- Crystal Structure
Moldoveanu et al. (2008) reported the 3.0-angstrom crystal structure of
calcium-bound m-calpain (CAPN2; 114230) in complex with the first
calpastatin repeat, both from rat, revealing the mechanism of exclusive
specificity. The structure highlighted the complexity of calpain
activation by calcium, illustrating key residues in a peripheral domain
that serve to stabilize the protease core on calcium binding. Fully
activated calpain binds 10 Ca(2+) atoms, resulting in several
conformational changes allowing recognition by calpastatin. Calpain
inhibition is mediated by the intimate contact with 3 critical regions
of calpastatin. Two regions target the penta-EF-hand domains of calpain,
and the third occupies the substrate-binding cleft, projecting a loop
around the active site thiol to evade proteolysis.
Hanna et al. (2008) reported the 2.4-angstrom resolution crystal
structure of the calcium-bound calpain-2 (m-calpain) heterodimer bound
by 1 of the 4 inhibitory domains of calpastatin. They observed that
calpastatin inhibits calpain by occupying both sides of the active site
cleft. Although the inhibitor passes through the active site cleft it
escapes cleavage in a novel manner by looping out and around the active
site cysteine. The inhibitory domain of calpastatin recognizes multiple
lower affinity sites present only in the calcium-bound form of the
enzyme, resulting in an interaction that is tight, specific, and
calcium-dependent. Hanna et al. (2008) concluded that this crystal
structure, and that of the related complex described by Moldoveanu et
al. (2008), also revealed the conformational changes that calpain
undergoes on binding calcium, which include opening of the active site
cleft and movement of the domains relative to each other to produce a
more compact enzyme.
ANIMAL MODEL
Reduced sarcolemmal integrity in dystrophin (300377)-deficient muscles
of mdx mice and Duchenne muscular dystrophy (DMD; 310200) patients had
been reported to result in altered calcium homeostasis. Previous studies
had shown a correlative relationship between calpain activity in
dystrophic muscle and muscle necrosis, but had not tested whether
calpain activation precedes cell death or is a consequence of it.
Spencer and Mellgren (2002) generated mdx mice that overexpressed a
calpastatin transgene in muscle. Normal-appearing transgenic mice
overexpressing calpastatin were crossed with mdx mice. Two lines of mice
were examined, with different levels of calpastatin overexpression. Both
lines of transgenic/mdx mice showed reductions in muscle necrosis at 4
weeks of age. The extent of improvement correlated with the level of
calpastatin protein expression. Membrane damage, as assessed by procion
orange and creatine kinase assays, was unchanged, supporting the idea
that calpains act downstream of the primary muscle defect. The authors
hypothesized that calpains may play an active role in necrotic processes
in dystrophic muscle, and that inhibition of calpains might provide a
therapeutic option for treatment of DMD.
*FIELD* SA
Mellgren (2008)
*FIELD* RF
1. Hanna, R. A.; Campbell, R. L.; Davies, P. L.: Calcium-bound structure
of calpain and its mechanism of inhibition by calpastatin. Nature 456:
409-412, 2008.
2. Inazawa, J.; Nakagawa, H.; Misawa, S.; Abe, T.; Minoshima, S.;
Fukuyama, R.; Maki, M.; Murachi, T.; Hatanaka, M.; Shimizu, N.: Assignment
of the human calpastatin gene (CAST) to chromosome 5 at region q14-q22. Cytogenet.
Cell Genet. 54: 156-158, 1990.
3. Inazawa, J.; Nakagawa, H.; Misawa, S.; Abe, T.; Minoshima, S.;
Fukuyama, R.; Maki, M.; Murachi, T.; Hatanaka, M.; Shimizu, N.: Assignment
of the human calpastatin gene (CAST) to chromosome 5 at region q15-q21.
(Abstract) Cytogenet. Cell Genet. 58: 1898 only, 1991.
4. Mellgren, R. L.: Enzyme knocked for a loop. Nature 456: 337-338,
2008.
5. Mimori, T.; Suganuma, K.; Tanami, Y.; Nojima, T.; Matsumura, M.;
Fujii, T.; Yoshizawa, T.; Suzuki, K.; Akizuki, M.: Autoantibodies
to calpastatin (an endogenous inhibitor for calcium-dependent neutral
protease, calpain) in systemic rheumatic diseases. Proc. Nat. Acad.
Sci. 92: 7267-7271, 1995.
6. Moldoveanu, T.; Gehring, K.; Green, D. R.: Concerted multi-pronged
attack by calpastatin to occlude the catalytic cleft of heterodimeric
calpains. Nature 456: 404-408, 2008.
7. Pontremoli, S.; Salamino, F.; Sparatore, B.; De Tullio, R.; Pontremoli,
R.; Melloni, E.: Characterization of the calpastatin defect in erythrocytes
from patients with essential hypertension. Biochem. Biophys. Res.
Commun. 157: 867-874, 1988.
8. Spencer, M. J.; Mellgren, R. L.: Overexpression of a calpastatin
transgene in mdx muscle reduces dystrophic pathology. Hum. Molec.
Genet. 11: 2645-2655, 2002.
*FIELD* CN
Ada Hamosh - updated: 3/11/2009
George E. Tiller - updated: 2/5/2004
*FIELD* CD
Victor A. McKusick: 3/20/1989
*FIELD* ED
alopez: 03/16/2009
alopez: 3/16/2009
terry: 3/11/2009
cwells: 2/5/2004
mark: 9/19/1995
supermim: 3/16/1992
carol: 2/21/1992
carol: 8/8/1991
carol: 2/26/1991
supermim: 3/20/1990
*RECORD*
*FIELD* NO
114090
*FIELD* TI
*114090 CALPASTATIN; CAST
*FIELD* TX
DESCRIPTION
Calpastatin is an endogenous inhibitor of calpains (see 114170)
read moreconsisting of 4 inhibitory repeats, each of which neutralizes an
activated calpain. Unlike proteinases, it is an intrinsically
unstructured protein, adopting a defined structure only upon binding to
active calpain ().
GENE FUNCTION
In erythrocytes of patients with essential hypertension (see 145500),
the level of calpastatin activity is significantly lower than in the red
cells of normotensive subjects. Pontremoli et al. (1988) demonstrated by
Western blot analysis that the decreased inhibitor activity is the
result of a decrease in the amount of the inhibitor protein. Calpastatin
isolated and purified from erythrocytes of normotensive and hypertensive
patients had identical specific activities. Pontremoli et al. (1988)
also presented evidence indicating that the decreased level of
calpastatin cannot be ascribed to accelerated decay during the red cell
life span.
Mimori et al. (1995) demonstrated that anti-calpastatin autoantibodies
are present in as many as 57% of rheumatoid arthritis patients and
concluded that they may participate in pathogenic mechanisms of this and
other rheumatic diseases which showed a lower frequency.
MAPPING
Using a cDNA probe encoding the 5-prime terminal region of CAST for
spot-blot analysis of sorted chromosomes and chromosomal in situ
hybridization, Inazawa et al. (1990) assigned the CAST gene to 5q14-q22.
Inazawa et al. (1991) mapped CAST to 5q15-q21 by 2 methods of in situ
hybridization and confirmed the results by spot-blot analysis of sorted
chromosomes.
BIOCHEMICAL FEATURES
- Crystal Structure
Moldoveanu et al. (2008) reported the 3.0-angstrom crystal structure of
calcium-bound m-calpain (CAPN2; 114230) in complex with the first
calpastatin repeat, both from rat, revealing the mechanism of exclusive
specificity. The structure highlighted the complexity of calpain
activation by calcium, illustrating key residues in a peripheral domain
that serve to stabilize the protease core on calcium binding. Fully
activated calpain binds 10 Ca(2+) atoms, resulting in several
conformational changes allowing recognition by calpastatin. Calpain
inhibition is mediated by the intimate contact with 3 critical regions
of calpastatin. Two regions target the penta-EF-hand domains of calpain,
and the third occupies the substrate-binding cleft, projecting a loop
around the active site thiol to evade proteolysis.
Hanna et al. (2008) reported the 2.4-angstrom resolution crystal
structure of the calcium-bound calpain-2 (m-calpain) heterodimer bound
by 1 of the 4 inhibitory domains of calpastatin. They observed that
calpastatin inhibits calpain by occupying both sides of the active site
cleft. Although the inhibitor passes through the active site cleft it
escapes cleavage in a novel manner by looping out and around the active
site cysteine. The inhibitory domain of calpastatin recognizes multiple
lower affinity sites present only in the calcium-bound form of the
enzyme, resulting in an interaction that is tight, specific, and
calcium-dependent. Hanna et al. (2008) concluded that this crystal
structure, and that of the related complex described by Moldoveanu et
al. (2008), also revealed the conformational changes that calpain
undergoes on binding calcium, which include opening of the active site
cleft and movement of the domains relative to each other to produce a
more compact enzyme.
ANIMAL MODEL
Reduced sarcolemmal integrity in dystrophin (300377)-deficient muscles
of mdx mice and Duchenne muscular dystrophy (DMD; 310200) patients had
been reported to result in altered calcium homeostasis. Previous studies
had shown a correlative relationship between calpain activity in
dystrophic muscle and muscle necrosis, but had not tested whether
calpain activation precedes cell death or is a consequence of it.
Spencer and Mellgren (2002) generated mdx mice that overexpressed a
calpastatin transgene in muscle. Normal-appearing transgenic mice
overexpressing calpastatin were crossed with mdx mice. Two lines of mice
were examined, with different levels of calpastatin overexpression. Both
lines of transgenic/mdx mice showed reductions in muscle necrosis at 4
weeks of age. The extent of improvement correlated with the level of
calpastatin protein expression. Membrane damage, as assessed by procion
orange and creatine kinase assays, was unchanged, supporting the idea
that calpains act downstream of the primary muscle defect. The authors
hypothesized that calpains may play an active role in necrotic processes
in dystrophic muscle, and that inhibition of calpains might provide a
therapeutic option for treatment of DMD.
*FIELD* SA
Mellgren (2008)
*FIELD* RF
1. Hanna, R. A.; Campbell, R. L.; Davies, P. L.: Calcium-bound structure
of calpain and its mechanism of inhibition by calpastatin. Nature 456:
409-412, 2008.
2. Inazawa, J.; Nakagawa, H.; Misawa, S.; Abe, T.; Minoshima, S.;
Fukuyama, R.; Maki, M.; Murachi, T.; Hatanaka, M.; Shimizu, N.: Assignment
of the human calpastatin gene (CAST) to chromosome 5 at region q14-q22. Cytogenet.
Cell Genet. 54: 156-158, 1990.
3. Inazawa, J.; Nakagawa, H.; Misawa, S.; Abe, T.; Minoshima, S.;
Fukuyama, R.; Maki, M.; Murachi, T.; Hatanaka, M.; Shimizu, N.: Assignment
of the human calpastatin gene (CAST) to chromosome 5 at region q15-q21.
(Abstract) Cytogenet. Cell Genet. 58: 1898 only, 1991.
4. Mellgren, R. L.: Enzyme knocked for a loop. Nature 456: 337-338,
2008.
5. Mimori, T.; Suganuma, K.; Tanami, Y.; Nojima, T.; Matsumura, M.;
Fujii, T.; Yoshizawa, T.; Suzuki, K.; Akizuki, M.: Autoantibodies
to calpastatin (an endogenous inhibitor for calcium-dependent neutral
protease, calpain) in systemic rheumatic diseases. Proc. Nat. Acad.
Sci. 92: 7267-7271, 1995.
6. Moldoveanu, T.; Gehring, K.; Green, D. R.: Concerted multi-pronged
attack by calpastatin to occlude the catalytic cleft of heterodimeric
calpains. Nature 456: 404-408, 2008.
7. Pontremoli, S.; Salamino, F.; Sparatore, B.; De Tullio, R.; Pontremoli,
R.; Melloni, E.: Characterization of the calpastatin defect in erythrocytes
from patients with essential hypertension. Biochem. Biophys. Res.
Commun. 157: 867-874, 1988.
8. Spencer, M. J.; Mellgren, R. L.: Overexpression of a calpastatin
transgene in mdx muscle reduces dystrophic pathology. Hum. Molec.
Genet. 11: 2645-2655, 2002.
*FIELD* CN
Ada Hamosh - updated: 3/11/2009
George E. Tiller - updated: 2/5/2004
*FIELD* CD
Victor A. McKusick: 3/20/1989
*FIELD* ED
alopez: 03/16/2009
alopez: 3/16/2009
terry: 3/11/2009
cwells: 2/5/2004
mark: 9/19/1995
supermim: 3/16/1992
carol: 2/21/1992
carol: 8/8/1991
carol: 2/26/1991
supermim: 3/20/1990