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Reviewed, UniProtKB/Swiss-Prot Q92851 (CASPA_HUMAN)

Last modified November 25, 2008. Version 98. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Caspase-10
      Short name=CASP-10
    EC=3.4.22.63
Alternative name(s):
    ICE-like apoptotic protease 4
    Apoptotic protease Mch-4
    FAS-associated death domain protein interleukin-1B-converting enzyme 2
      Short name=FLICE2
Cleaved into the following 2 chains:
    1- Recommended name:
            Caspase-10 subunit p23/17
    2- Recommended name:
            Caspase-10 subunit p12
Gene names
Name: CASP10
Synonyms: MCH4
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length521 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

General annotation (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.

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 structure

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.

Tissue specificity

Detectable in most tissues. Lowest expression is seen in brain, kidney, prostate, testis and colon.

Post-translational modification

Cleavage by granzyme B and autocatalytic activity generate the two active subunits.

Phosphorylated upon DNA damage, probably by ATM or ATR.

Involvement in 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.

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.

Defects in CASP10 are a cause of gastric cancers [MIM:137215].

Sequence similarities

Belongs to the peptidase C14 family.

Contains 2 DED (death effector) domains.

Ontologies

Keywords

   Biological processApoptosis
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainRepeat
   Molecular functionHydrolase
Protease
Thiol protease
   PTMPhosphoprotein
Zymogen
   Technical termDirect protein sequencing

Gene Ontology (GO)

   Biological processinduction of apoptosis by extracellular signals

Inferred from Experiment. Source: Reactome

proteolysis

Inferred from electronic annotation. Source: InterPro

   Molecular functioncysteine-type endopeptidase activity Ref.1 Ref.9

Traceable author statement. Source: ProtInc

identical protein binding Ref.6

Inferred from physical interaction. Source: IntAct

Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]
Isoform A (identifier: Q92851-1)

Also known as: 10-A;

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.
Isoform B (identifier: Q92851-2)

Also known as: 10-B; 10-S;

The sequence of this isoform differs from the canonical sequence as follows:
     229-271: Missing.
     473-521: MLKFLEKTME...PPMRRWSSVS → HEDILSILTA...FPVPLDALSI
Notes: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Isoform D (identifier: Q92851-4)

Also known as: 10-D; 10-L;

The sequence of this isoform differs from the canonical sequence as follows:
     473-521: MLKFLEKTME...PPMRRWSSVS → HEDILSILTA...FPVPLDALSI
Isoform C (identifier: Q92851-3)

Also known as: 10-C;

The sequence of this isoform differs from the canonical sequence as follows:
     241-273: GNRATNGAPSLVSRGMQGASANTLNSETSTKRA → EGSCVQDESEPQRPLCHCQQPQLYLPEGQTRNP
     274-521: Missing.
Notes: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Propeptide1 – 219219
PRO_0000004644
Chain220 – 415196Caspase-10 subunit p23/17
PRO_0000004645
Chain416 – 521106Caspase-10 subunit p12
PRO_0000004646

Regions

Domain19 – 9779DED 1
Domain114 – 18774DED 2

Sites

Active site3581 By similarity
Active site4011 By similarity

Amino acid modifications

Modified residue2161Phosphoserine

Natural variations

Alternative sequence229 – 27143Missing in isoform B.
VSP_000819
Alternative sequence241 – 27333GNRAT…STKRA → EGSCVQDESEPQRPLCHCQQ PQLYLPEGQTRNP in isoform C.
VSP_000821
Alternative sequence274 – 521248Missing in isoform C.
VSP_000822
Alternative sequence473 – 52149MLKFL…WSSVS → HEDILSILTAVNDDVSRRVD KQGTKKQMPQPAFTLRKKLV FPVPLDALSI in isoform B and isoform D.
VSP_000820
Natural variant1471M → T in gastric cancer; somatic mutation; impairs CASP10-mediated apoptosis.
VAR_037428
Natural variant2851L → F in ALPS2A. dbSNP rs17860403.
VAR_014071
Natural variant4061I → L in ALPS2A; the mutant protein has defective apoptosis and exerts a dominant-negative effect when cotransfected with the wild-type protein.
VAR_037429
Natural variant4101V → I: dbSNP rs13010627.
VAR_014072
Natural variant4141A → V in NHL; somatic mutation. dbSNP rs28936699.
VAR_037430
Natural variant4461Y → C: dbSNP rs17860405.
VAR_037431

Experimental info

Mutagenesis4011C → A: Abolishes proteolytic activity
Sequence conflict681E → G in AAB46730. Ref.2
Sequence conflict2681T → A in AAD28403. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Isoform A (10-A) [UniParc].

Last modified January 11, 2001. Version 3.
Checksum: 840348AE602B8243

FASTA52158,951
        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 

« Hide

Isoform B (10-B) (10-S) [UniParc].

Checksum: 1317FD7A4EE003FF
Show »

47954,566
Isoform D (10-D) (10-L) [UniParc].

Checksum: 33F47E07B3DFA688
Show »

52258,994
Isoform C (10-C) [UniParc].

Checksum: 1146630514EE38DC
Show »

27331,419

References

« Hide 'large scale' references
[1]"In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains."
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.
Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996) [PubMed: 8755496] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
Tissue: T-cell.
[2]"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."
Vincenz C., Dixit V.M.
J. Biol. Chem. 272:6578-6583(1997) [PubMed: 9045686] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
[3]"Molecular cloning and characterization of two novel pro-apoptotic isoforms of caspase-10."
Ng P.W., Porter A.G., Janicke R.U.
J. Biol. Chem. 274:10301-10308(1999) [PubMed: 10187817] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS C AND D), VARIANT ILE-410.
Tissue: Spleen and Thymus.
[4]"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."
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.
Genomics 71:200-213(2001) [PubMed: 11161814] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING (ISOFORMS A AND B).
[5]"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."
Srinivasula S.M., Ahmad M., Fernandes-Alnemri T., Litwack G., Alnemri E.S.
Proc. Natl. Acad. Sci. U.S.A. 93:14486-14491(1996) [PubMed: 8962078] [Abstract]
Cited for: PARTIAL PROTEIN SEQUENCE, PROTEOLYTIC PROCESSING.
[6]"Caspase-10 is an initiator caspase in death receptor signaling."
Wang J., Chun H.J., Wong W., Spencer D.M., Lenardo M.J.
Proc. Natl. Acad. Sci. U.S.A. 98:13884-13888(2001) [PubMed: 11717445] [Abstract]
Cited for: FUNCTION, SELF-ASSOCIATION, INTERACTION WITH FADD, INTERACTION WITH CASP8, IDENTIFICATION IN A COMPLEX WITH FAS; FADD AND CASP8, MUTAGENESIS OF CYS-401.
[7]"An unappreciated role for RNA surveillance."
Hillman R.T., Green R.E., Brenner S.E.
Genome Biol. 5:RESEARCH008.1-RESEARCH008.16(2004) [PubMed: 14759258] [Abstract]
Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
[8]"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage."
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.
Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-216, MASS SPECTROMETRY.
[9]"Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II."
Wang J., Zheng L., Lobito A., Chan F.K., Dale J., Sneller M., Yao X., Puck J.M., Straus S.E., Lenardo M.J.
Cell 98:47-58(1999) [PubMed: 10412980] [Abstract]
Cited for: ALTERNATIVE SPLICING (ISOFORMS B AND D), VARIANT ALPS2A PHE-285, VARIANT ILE-410.
[10]"Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas."
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.
Blood 99:4094-4099(2002) [PubMed: 12010812] [Abstract]
Cited for: VARIANT NHL VAL-414.
[11]"Inactivating mutations of the caspase-10 gene in gastric cancer."
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.
Oncogene 21:2919-2925(2002) [PubMed: 11973654] [Abstract]
Cited for: VARIANT GASTRIC CANCER THR-147, CHARACTERIZATION OF VARIANT GASTRIC CANCER THR-147.
[12]"Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome."
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.
Hum. Genet. 119:284-294(2006) [PubMed: 16446975] [Abstract]
Cited for: VARIANT ALPS2A LEU-406, CHARACTERIZATION OF VARIANT ALPS2A LEU-406.
+Additional computationally mapped references.

Web resources

CASP10base

CASP10 mutation db

Autoimmune Lymphoproliferative Syndrome Database (ALPSbase)

Caspase-10 mutations causing ALPS type II

GeneReviews

Cross-references

Sequence databases

U60519 mRNA. Translation: AAC50644.1.
U86214 mRNA. Translation: AAB46730.1.
AF111344 mRNA. Translation: AAD28402.1.
AF111345 mRNA. Translation: AAD28403.1.
AB038979 Genomic DNA. Translation: BAB32553.1.
AB038979 Genomic DNA. Translation: BAB32554.1.
RefSeqNP_001221.2.
NP_116756.2.
UniGeneHs.5353

3D structure databases

HSSPHSSP built from PDB template 1QTN based on UniProtKB Q9C0K4.
ModBaseSearch...

Protein-protein interaction databases

IntActQ92851.

Protein family/group databases

MEROPSC14.011.

PTM databases

PhosphoSiteQ92851.

Genome annotation databases

EnsemblENSG00000003400. Homo sapiens. [Contig view]
GeneID843.
KEGGhsa:843.

Organism-specific databases

HGNCHGNC:1500. CASP10.
HPACAB003780.
HPA017059.
MIM137215. phenotype.
601762. gene.
603909. phenotype.
605027. phenotype.
Orphanet3261. Autoimmune lymphoproliferative syndrome.
26106. Gastric cancer, familial.
PharmGKBPA26084.
GenAtlasSearch...
GeneCardsSearch...

Phylogenomic databases

HOVERGENQ92851.

Enzyme and pathway databases

ReactomeREACT_578. Apoptosis.

Gene expression databases

ArrayExpressQ92851.
CleanExHS_CASP10.
GermOnlineENSG00000003400. Homo sapiens.

Family and domain databases

InterProIPR011029. 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]
Gene3DG3DSA:1.10.533.10. DEATH_like. 2 hits.
PANTHERPTHR10454. Pept_C14_p45. 1 hit.
PfamPF01335. DED. 2 hits.
PF00656. Peptidase_C14. 1 hit.
[Graphical view]
PRINTSPR00376. IL1BCENZYME.
SMARTSM00115. CASc. 1 hit.
SM00031. DED. 2 hits.
[Graphical view]
PROSITEPS01122. CASPASE_CYS. 1 hit.
PS01121. CASPASE_HIS. 1 hit.
PS50207. CASPASE_P10. 1 hit.
PS50208. CASPASE_P20. 1 hit.
PS50168. DED. 2 hits.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio3530.
SOURCESearch...

Entry information

Entry nameCASPA_HUMAN
AccessionPrimary (citable) accession number: Q92851
Secondary accession number(s): Q8WYQ8 expand/collapse secondary AC list , Q99845, Q9Y2U6, Q9Y2U7
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: January 11, 2001
Last modified: November 25, 2008
This is version 98 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Peptidase families

Classification of peptidase families and list of entries

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents