Caspase-10 precursor - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot Q92851 (CASPA_HUMAN)

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

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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

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Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	521 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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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.

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Ontologies

Keywords
Biological process	Apoptosis
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat
Molecular function	Hydrolase Protease Thiol protease
PTM	Phosphoprotein Zymogen
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	induction of apoptosis by extracellular signals Inferred from Experiment. Source: Reactome proteolysis Inferred from electronic annotation. Source: InterPro
Molecular function	cysteine-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...

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Binary interactions

With	Entry	#Exp.	IntAct
itself		1	EBI-495095,EBI-495095
itself		1	EBI-495122,EBI-495122
CASP8	Q14790	2	EBI-495095,EBI-78060
EDA2R	Q9HAV5	1	EBI-495122,EBI-526033
FADD	Q13158	1	EBI-495095,EBI-494804

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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.

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Propeptide

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

Regions

Domain

19 – 97

DED 1

Domain

114 – 187

DED 2

Sites

Active site

358

By similarity

Active site

401

By similarity

Amino acid modifications

Modified residue

216

Phosphoserine

Natural variations

Alternative sequence

229 – 271

Missing in isoform B.

VSP_000819

Alternative sequence

241 – 273

GNRAT…STKRA → EGSCVQDESEPQRPLCHCQQ PQLYLPEGQTRNP in isoform C.

VSP_000821

Alternative sequence

274 – 521

248

Missing in isoform C.

VSP_000822

Alternative sequence

473 – 521

MLKFL…WSSVS → HEDILSILTAVNDDVSRRVD KQGTKKQMPQPAFTLRKKLV FPVPLDALSI in isoform B and isoform D.

VSP_000820

Natural variant

147

M → T in gastric cancer; somatic mutation; impairs CASP10-mediated apoptosis.

VAR_037428

Natural variant

285

L → F in ALPS2A. dbSNP rs17860403.

VAR_014071

Natural variant

406

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

Natural variant

410

V → I: dbSNP rs13010627.

VAR_014072

Natural variant

414

A → V in NHL; somatic mutation. dbSNP rs28936699.

VAR_037430

Natural variant

446

Y → C: dbSNP rs17860405.

VAR_037431

Experimental info

Mutagenesis

401

C → A: Abolishes proteolytic activity

Sequence conflict

E → G in AAB46730. Ref.2

Sequence conflict

268

T → A in AAD28403. Ref.3

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Sequences

Sequence		Length	Mass (Da)
Isoform A (10-A) [UniParc]. Last modified January 11, 2001. Version 3. Checksum: 840348AE602B8243 Show »	FASTA	521	58,951
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 »		479	54,566
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 KTFLEALPRA AVYRMNRNHR 250 260 270 280 290 300 GLCVIVNNHS FTSLKDRQGT HKDAEILSHV FQWLGFTVHI HNNVTKVEME MVLQKQKCNP 310 320 330 340 350 360 AHADGDCFVF CILTHGRFGA VYSSDEALIP IREIMSHFTA LQCPRLAEKP KLFFIQACQG 370 380 390 400 410 420 EEIQPSVSIE ADALNPEQAP TSLQDSIPAE ADFLLGLATV PGYVSFRHVE EGSWYIQSLC 430 440 450 460 470 NHLKKLVPRH EDILSILTAV NDDVSRRVDK QGTKKQMPQP AFTLRKKLVF PVPLDALSI « Hide
Isoform D (10-D) (10-L) [UniParc]. Checksum: 33F47E07B3DFA688 Show »		522	58,994
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 PRHEDILSIL 490 500 510 520 TAVNDDVSRR VDKQGTKKQM PQPAFTLRKK LVFPVPLDAL SI « Hide
Isoform C (10-C) [UniParc]. Checksum: 1146630514EE38DC Show »		273	31,419
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 EGSCVQDESE PQRPLCHCQQ PQLYLPEGQT RNP « Hide

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References

	« Hide 'large scale' referencesShow '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.

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Web resources

CASP10base

CASP10 mutation db

Autoimmune Lymphoproliferative Syndrome Database (ALPSbase)

Caspase-10 mutations causing ALPS type II

GeneReviews

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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.
RefSeq	NP_001221.2. NP_116756.2.
UniGene	Hs.5353
3D structure databases
HSSP	HSSP built from PDB template 1QTN based on UniProtKB Q9C0K4.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q92851.
Protein family/group databases
MEROPS	C14.011.
PTM databases
PhosphoSite	Q92851.
Genome annotation databases
Ensembl	ENSG00000003400. Homo sapiens. [Contig view]
GeneID	843.
KEGG	hsa:843.
Organism-specific databases
HGNC	HGNC:1500. CASP10.
HPA	CAB003780. HPA017059.
MIM	137215. phenotype. 601762. gene. 603909. phenotype. 605027. phenotype.
Orphanet	3261. Autoimmune lymphoproliferative syndrome. 26106. Gastric cancer, familial.
PharmGKB	PA26084.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOVERGEN	Q92851.
Enzyme and pathway databases
Reactome	REACT_578. Apoptosis.
Gene expression databases
ArrayExpress	Q92851.
CleanEx	HS_CASP10.
GermOnline	ENSG00000003400. Homo sapiens.
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]
Gene3D	G3DSA:1.10.533.10. DEATH_like. 2 hits.
PANTHER	PTHR10454. Pept_C14_p45. 1 hit.
Pfam	PF01335. DED. 2 hits. PF00656. Peptidase_C14. 1 hit. [Graphical view]
PRINTS	PR00376. IL1BCENZYME.
SMART	SM00115. CASc. 1 hit. SM00031. DED. 2 hits. [Graphical view]
PROSITE	PS01122. 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]
ProtoNet	Search...
Other Resources
NextBio	3530.
SOURCE	Search...

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Entry information

Entry name

CASPA_HUMAN

Accession

Primary (citable) accession number: Q92851
Secondary accession number(s): Q8WYQ8

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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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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

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Alternative products

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

Protein family/group databases

PTM databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents