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UniProtKB/Swiss-Prot entry Q92851

[Entry info] [Name and origin] [References] [Comments] [Cross-references] [Keywords] [Features] [Sequence] [Tools]

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Entry information
Entry name CASPA_HUMAN
Primary accession number Q92851
Secondary accession numbers Q8WYQ8 Q99845 Q9Y2U6 Q9Y2U7
Integrated into Swiss-Prot on November 1, 1997
Sequence was last modified on January 11, 2001 (Sequence version 3)
Annotations were last modified on    July 22, 2008 (Entry version 96)
Name and origin of the protein
Protein name Caspase-10 [Precursor]
Synonyms CASP-10
EC 3.4.22.63
ICE-like apoptotic protease 4
Apoptotic protease Mch-4
FAS-associated death domain protein interleukin-1B-converting enzyme 2
FLICE2
Contains Caspase-10 subunit p23/17
Caspase-10 subunit p12
Gene name
Name: CASP10
Synonyms: MCH4
From
Homo sapiens (Human) [TaxID: 9606] 
Taxonomy Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.
Protein existence 1: Evidence at protein level;
References
[1]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
TISSUE=T-cell;
DOI=10.1073/pnas.93.15.7464; PubMed=8755496 [NCBI, ExPASy, EBI, Israel, Japan]
Fernandes-Alnemri T., Armstrong R.C., Krebs J.F., Srinivasula S.M., Wang L., Bullrich F., Fritz L.C., Trapani J.A., Tomaselli K.J., Litwack G., Alnemri E.S.;
"In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains.";
Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996).
[2]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
DOI=10.1074/jbc.272.10.6578; PubMed=9045686 [NCBI, ExPASy, EBI, Israel, Japan]
Vincenz C., Dixit V.M.;
"Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling.";
J. Biol. Chem. 272:6578-6583(1997).
[3]
 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS C AND D), AND VARIANT ILE-410.
TISSUE=Spleen, and Thymus;
DOI=10.1074/jbc.274.15.10301; PubMed=10187817 [NCBI, ExPASy, EBI, Israel, Japan]
Ng P.W., Porter A.G., Janicke R.U.;
"Molecular cloning and characterization of two novel pro-apoptotic isoforms of caspase-10.";
J. Biol. Chem. 274:10301-10308(1999).
[4]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING (ISOFORMS A AND B).
DOI=10.1006/geno.2000.6392; PubMed=11161814 [NCBI, ExPASy, EBI, Israel, Japan]
Hadano S., Yanagisawa Y., Skaug J., Fichter K., Nasir J., Martindale D., Koop B.F., Scherer S.W., Nicholson D.W., Rouleau G.A., Ikeda J.-E., Hayden M.R.;
"Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33-q34: candidate genes for ALS2.";
Genomics 71:200-213(2001).
[5]
 PARTIAL PROTEIN SEQUENCE, AND PROTEOLYTIC PROCESSING.
DOI=10.1073/pnas.93.25.14486; PubMed=8962078 [NCBI, ExPASy, EBI, Israel, Japan]
Srinivasula S.M., Ahmad M., Fernandes-Alnemri T., Litwack G., Alnemri E.S.;
"Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases.";
Proc. Natl. Acad. Sci. U.S.A. 93:14486-14491(1996).
[6]
 FUNCTION, SELF-ASSOCIATION, INTERACTION WITH FADD, INTERACTION WITH CASP8, IDENTIFICATION IN A COMPLEX WITH FAS; FADD AND CASP8, AND MUTAGENESIS OF CYS-401.
DOI=10.1073/pnas.241358198; PubMed=11717445 [NCBI, ExPASy, EBI, Israel, Japan]
Wang J., Chun H.J., Wong W., Spencer D.M., Lenardo M.J.;
"Caspase-10 is an initiator caspase in death receptor signaling.";
Proc. Natl. Acad. Sci. U.S.A. 98:13884-13888(2001).
[7]
 SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
DOI=10.1186/gb-2004-5-2-r8; PubMed=14759258 [NCBI, ExPASy, EBI, Israel, Japan]
Hillman R.T., Green R.E., Brenner S.E.;
"An unappreciated role for RNA surveillance.";
Genome Biol. 5:RESEARCH008.1-RESEARCH008.16(2004).
[8]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-216, AND MASS SPECTROMETRY.
DOI=10.1126/science.1140321; PubMed=17525332 [NCBI, ExPASy, EBI, Israel, Japan]
Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.";
Science 316:1160-1166(2007).
[9]
 ALTERNATIVE SPLICING (ISOFORMS B AND D), VARIANT ALPS2A PHE-285, AND VARIANT ILE-410.
DOI=10.1016/S0092-8674(00)80605-4; PubMed=10412980 [NCBI, ExPASy, EBI, Israel, Japan]
Wang J., Zheng L., Lobito A., Chan F.K., Dale J., Sneller M., Yao X., Puck J.M., Straus S.E., Lenardo M.J.;
"Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II.";
Cell 98:47-58(1999).
[10]
 VARIANT NHL VAL-414.
DOI=10.1182/blood.V99.11.4094; PubMed=12010812 [NCBI, ExPASy, EBI, Israel, Japan]
Shin M.S., Kim H.S., Kang C.S., Park W.S., Kim S.Y., Lee S.N., Lee J.H., Park J.Y., Jang J.J., Kim C.W., Kim S.H., Lee J.Y., Yoo N.J., Lee S.H.;
"Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas.";
Blood 99:4094-4099(2002).
[11]
 VARIANT GASTRIC CANCER THR-147, AND CHARACTERIZATION OF VARIANT GASTRIC CANCER THR-147.
DOI=10.1038/sj.onc.1205394; PubMed=11973654 [NCBI, ExPASy, EBI, Israel, Japan]
Park W.S., Lee J.H., Shin M.S., Park J.Y., Kim H.S., Lee J.H., Kim Y.S., Lee S.N., Xiao W., Park C.H., Lee S.H., Yoo N.J., Lee J.Y.;
"Inactivating mutations of the caspase-10 gene in gastric cancer.";
Oncogene 21:2919-2925(2002).
[12]
 VARIANT ALPS2A LEU-406, AND CHARACTERIZATION OF VARIANT ALPS2A LEU-406.
DOI=10.1007/s00439-006-0138-9; PubMed=16446975 [NCBI, ExPASy, EBI, Israel, Japan]
Zhu S., Hsu A.P., Vacek M.M., Zheng L., Schaeffer A.A., Dale J.K., Davis J., Fischer R.E., Straus S.E., Boruchov D., Saulsbury F.T., Lenardo M.J., Puck J.M.;
"Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome.";
Hum. Genet. 119:284-294(2006).
Comments
  • FUNCTION: Involved in the activation cascade of caspases responsible for apoptosis execution. Recruited to both Fas- and TNFR-1 receptors in a FADD dependent manner. May participate in the granzyme B apoptotic pathways. Cleaves and activates caspase-3, -4, -6, -7, -8, and -9. Hydrolyzes the small- molecule substrates, Tyr-Val-Ala-Asp-|-AMC and Asp-Glu-Val-Asp-|-AMC.
  • FUNCTION: Isoform C is proteolytically inactive.
  • CATALYTIC ACTIVITY: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Leu-Gln-Thr-Asp-|-Gly.
  • SUBUNIT: Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 23/17 kDa (p23/17) (depending on the splicing events) and a 12 kDa (p12) subunit (By similarity). Self-associates. Interacts with FADD and CASP8. Found in a Fas signaling complex consisting of FAS, FADD, CASP8 and CASP10.
  • INTERACTION:
    Self; NbExp=1; IntAct=EBI-495095, EBI-495095;
    Self; NbExp=1; IntAct=EBI-495122, EBI-495122;
    Q14790:CASP8; NbExp=2; IntAct=EBI-495095, EBI-78060;
    Q9HAV5:EDA2R; NbExp=1; IntAct=EBI-495122, EBI-526033;
    Q13158:FADD; NbExp=1; IntAct=EBI-495095, EBI-494804;
  • ALTERNATIVE PRODUCTS: 4 named isoforms [FASTA] produced by alternative splicing.
    NameA
    Synonyms10-A
    Isoform IDQ92851-1
    This is the isoform sequence displayed in this entry.
    NameB
    Synonyms10-B, 10-S
    Isoform IDQ92851-2
    Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
    Features which should be applied to build the isoform sequence: VSP_000819, VSP_000820.
    NameD
    Synonyms10-D, 10-L
    Isoform IDQ92851-4
    Features which should be applied to build the isoform sequence: VSP_000820.
    NameC
    Synonyms10-C
    Isoform IDQ92851-3
    Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
    Features which should be applied to build the isoform sequence: VSP_000821, VSP_000822.
  • TISSUE SPECIFICITY: Detectable in most tissues. Lowest expression is seen in brain, kidney, prostate, testis and colon.
  • PTM: Cleavage by granzyme B and autocatalytic activity generate the two active subunits.
  • PTM: Phosphorylated upon DNA damage, probably by ATM or ATR.
  • DISEASE: Defects in CASP10 are the cause of autoimmune lymphoproliferative syndrome type 2A (ALPS2A) [MIM:603909]. ALPS2 is characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects.
  • DISEASE: Defects in CASP10 are a cause of familial non-Hodgkin lymphoma (NHL) [MIM:605027]. NHL is a cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss.
  • DISEASE: Defects in CASP10 are a cause of gastric cancers [MIM:137215].
  • SIMILARITY: Belongs to the peptidase C14 family [view classification].
  • SIMILARITY: Contains 2 DED (death effector) domains.
  • WEB RESOURCE: Name=CASP10base; Note=CASP10 mutation db; URL="http://bioinf.uta.fi/CASP10base/";.
  • WEB RESOURCE: Name=Autoimmune Lymphoproliferative Syndrome Database (ALPSbase); Note=Caspase-10 mutations causing ALPS type II; URL="http://research.nhgri.nih.gov/ALPS/alpsII_mut.shtml";.
  • WEB RESOURCE: Name=GeneReviews; URL="http://www.genetests.org/query?gene=CASP10";.
Copyright
Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.
Cross-references
Sequence databases
EMBL
U60519; AAC50644.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
U86214; AAB46730.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AF111344; AAD28402.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AF111345; AAD28403.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AB038979; BAB32553.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
AB038979; BAB32554.1; -; Genomic_DNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
RefSeq NP_001221.2; -.
NP_116756.2; -.
UniGene Hs.5353
3D structure databases
HSSP Q9C0K4; 1QTN. [HSSP ENTRY / PDB]
ModBase Q92851.
Protein-protein interaction databases
IntAct Q92851; -.
Protein family/group databases
MEROPS C14.011; -.
PTM databases
PhosphoSite Q92851; -.
Enzyme and pathway databases
Reactome REACT_578; Apoptosis.
Organism-specific databases
HGNC HGNC:1500; CASP10.
GenAtlas CASP10.
HPA CAB003780; -.
HPA017059; -.
MIM 137215; phenotype. [NCBI / EBI]
601762; gene. [NCBI / EBI]
603909; phenotype. [NCBI / EBI]
605027; phenotype. [NCBI / EBI]
Orphanet 3261; Autoimmune lymphoproliferative syndrome.
26106; Gastric cancer, familial.
PharmGKB PA26084; -.
GeneCards Q92851.
Gene expression databases
ArrayExpress Q92851; -.
CleanEx HS_CASP10; -.
GermOnline ENSG00000003400; Homo sapiens.
Ontologies
GO
GO:0030693; Molecular function: caspase activity (traceable author statement from ProtInc).
GO:0042802; Molecular function: identical protein binding (inferred from physical interaction from IntAct).
GO:0008624; Biological process: induction of apoptosis by extracellular signals (inferred from experiment from Reactome).
QuickGo view.
Family and domain databases
InterPro IPR011029; DEATH_like.
IPR001875; DED.
IPR011600; Pept_C14_cat.
IPR001309; Pept_C14_ICE_p20.
IPR016129; Pept_C14_ICE_p20_AS.
IPR002138; Pept_C14_p10.
IPR002398; Pept_C14_p45.
IPR015917; Pept_C14_p45_core.
Graphical view of domain structure.
Gene3D G3DSA:1.10.533.10; DEATH_like; 2.
PANTHER PTHR10454; Pept_C14_p45; 1.
Pfam PF01335; DED; 2.
PF00656; Peptidase_C14; 1.
Pfam graphical view of domain structure.
PRINTS PR00376; IL1BCENZYME.
SMART SM00115; CASc; 1.
SM00031; DED; 2.
SMART graphical view of domain structure.
PROSITE PS01122; CASPASE_CYS; 1.
PS01121; CASPASE_HIS; 1.
PS50207; CASPASE_P10; 1.
PS50208; CASPASE_P20; 1.
PS50168; DED; 2.
PROSITE graphical view of domain structure (profiles).
BLOCKS Q92851.
Genome annotation databases
Ensembl ENSG00000003400; Homo sapiens. [Contig view]
GeneID 843; -.
KEGG hsa:843; -.
Phylogenomic databases
HOVERGEN Q92851; -.
Other
SOURCE CASP10; Homo sapiens.
ProtoNet Q92851.
UniRef View cluster of proteins with at least 50% / 90% / 100% identity.
Keywords
Alternative splicing; Apoptosis; Direct protein sequencing; Disease mutation; Hydrolase; Phosphoprotein; Polymorphism; Protease; Repeat; Thiol protease; Zymogen.
Features
SEVIEWER logo Feature table viewer FT aligner logo Feature aligner
KeyFrom   To Length Description FTId
PROPEP   1   219  219      PRO_0000004644
CHAIN   220   415  196     Caspase-10 subunit p23/17. PRO_0000004645
CHAIN   416   521  106     Caspase-10 subunit p12. PRO_0000004646
DOMAIN   19    97  79     DED 1. 
DOMAIN   114   187  74     DED 2. 
ACT_SITE   358   358        By similarity. 
ACT_SITE   401   401        By similarity. 
MOD_RES   216   216        Phosphoserine. 
VAR_SEQ   229   271        Missing (in isoform B). VSP_000819
VAR_SEQ   241   273        GNRATNGAPSLVSRGMQGASANTLNSETSTKRA -> EGSCVQDESEPQRPLCHCQQPQLYLPEGQTRNP (in isoform C). VSP_000821
VAR_SEQ   274   521        Missing (in isoform C). VSP_000822
VAR_SEQ   473   521        MLKFLEKTMEIRGRKRTVWGAKQISATSLPTAISAQTPRP PMRRWSSVS -> HEDILSILTAVNDDVSRRVDKQGTKKQMPQPAFTLRKKLV FPVPLDALSI (in isoform B and isoform D). VSP_000820
VARIANT   147   147  1     M -> T (in gastric cancer; somatic mutation; impairs CASP10-mediated apoptosis). VAR_037428 
VARIANT   285   285  1     L -> F (in ALPS2A; dbSNP:rs17860403 [NCBI]). VAR_014071 
VARIANT   406   406  1     I -> L (in ALPS2A; the mutant protein has defective apoptosis and exerts a dominant-negative effect when cotransfected with the wild-type protein). VAR_037429 
VARIANT   410   410  1     V -> I (in dbSNP:rs13010627 [NCBI]). VAR_014072 
VARIANT   414   414  1     A -> V (in NHL; somatic mutation; dbSNP:rs28936699 [NCBI]). VAR_037430 
VARIANT   446   446  1     Y -> C (in dbSNP:rs17860405 [NCBI]). VAR_037431 
MUTAGEN   401   401        C->A: Abolishes proteolytic activity. 
CONFLICT   68    68        E -> G (in Ref. 2; AAB46730). 
CONFLICT   268   268        T -> A (in Ref. 3; AAD28403). 
Sequence information
Length: 521 AA [This is the length of the unprocessed precursor] Molecular weight: 58951 Da [This is the MW of the unprocessed precursor] CRC64: 840348AE602B8243 [This is a checksum on the sequence] 
        10         20         30         40         50         60 
MKSQGQHWYS SSDKNCKVSF REKLLIIDSN LGVQDVENLK FLCIGLVPNK KLEKSSSASD 

        70         80         90        100        110        120 
VFEHLLAEDL LSEEDPFFLA ELLYIIRQKK LLQHLNCTKE EVERLLPTRQ RVSLFRNLLY 

       130        140        150        160        170        180 
ELSEGIDSEN LKDMIFLLKD SLPKTEMTSL SFLAFLEKQG KIDEDNLTCL EDLCKTVVPK 

       190        200        210        220        230        240 
LLRNIEKYKR EKAIQIVTPP VDKEAESYQG EEELVSQTDV KTFLEALPQE SWQNKHAGSN 

       250        260        270        280        290        300 
GNRATNGAPS LVSRGMQGAS ANTLNSETST KRAAVYRMNR NHRGLCVIVN NHSFTSLKDR 

       310        320        330        340        350        360 
QGTHKDAEIL SHVFQWLGFT VHIHNNVTKV EMEMVLQKQK CNPAHADGDC FVFCILTHGR 

       370        380        390        400        410        420 
FGAVYSSDEA LIPIREIMSH FTALQCPRLA EKPKLFFIQA CQGEEIQPSV SIEADALNPE 

       430        440        450        460        470        480 
QAPTSLQDSI PAEADFLLGL ATVPGYVSFR HVEEGSWYIQ SLCNHLKKLV PRMLKFLEKT 

       490        500        510        520 
MEIRGRKRTV WGAKQISATS LPTAISAQTP RPPMRRWSSV S
Q92851 in FASTA format

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