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Reviewed, UniProtKB/Swiss-Prot Q14790 (CASP8_HUMAN)

Last modified November 25, 2008. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (8) | 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

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Names and origin

Protein namesRecommended name:
    Caspase-8
      Short name=CASP-8
    EC=3.4.22.61
Alternative name(s):
    ICE-like apoptotic protease 5
    MORT1-associated CED-3 homolog
      Short name=MACH
    FADD-homologous ICE/CED-3-like protease
    FADD-like ICE
      Short name=FLICE
    Apoptotic cysteine protease
    Apoptotic protease Mch-5
    CAP4
Cleaved into the following 2 chains:
    1- Recommended name:
            Caspase-8 subunit p18
    2- Recommended name:
            Caspase-8 subunit p10
Gene names
Name: CASP8
Synonyms: MCH5
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length479 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

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General annotation (Comments)

Function

Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoforms 5, 6, 7 and 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.

Catalytic activity

Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).

Subunit structure

Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2 By similarity.

Subcellular location

Cytoplasm.

Tissue specificity

Isoforms 1, 5 and 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus, and liver. Barely detectable in brain, testis, and skeletal muscle.

Domain

Isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex.

Post-translational modification

Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events.

Phosphorylated upon DNA damage, probably by ATM or ATR.

Polymorphism

Genetic vaiations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic vaiations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner.

Involvement in disease

Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:607271]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.

Sequence similarities

Belongs to the peptidase C14 family.

Contains 2 DED (death effector) domains.

Sequence caution

The sequence CAA66858.1 differs from that shown. Reason: Miscellaneous discrepancy.

The sequence CAA66859.1 differs from that shown. Reason: Miscellaneous discrepancy.

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Alternative products

This entry describes 9 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q14790-1)

Also known as: Alpha-1;

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 2 (identifier: Q14790-2)

Also known as: Alpha-2; MCH5-beta;

The sequence of this isoform differs from the canonical sequence as follows:
     184-198: Missing.
Isoform 3 (identifier: Q14790-3)

Also known as: Alpha-3;

The sequence of this isoform differs from the canonical sequence as follows:
     184-267: Missing.
Isoform 4 (identifier: Q14790-4)

Also known as: Alpha-4;

The sequence of this isoform differs from the canonical sequence as follows:
     102-102: R → RFHFCRMSWAEANSQCQTQSVPFWRRVDHLLIR
     184-198: Missing.
Isoform 5 (identifier: Q14790-5)

Also known as: Beta-1;

The sequence of this isoform differs from the canonical sequence as follows:
     199-235: GEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGY → DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH
     236-479: Missing.
Isoform 6 (identifier: Q14790-6)

Also known as: Beta-2;

The sequence of this isoform differs from the canonical sequence as follows:
     184-220: ERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQ → DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH
     221-479: Missing.
Isoform 7 (identifier: Q14790-7)

Also known as: Beta-3; 8L;

The sequence of this isoform differs from the canonical sequence as follows:
     269-276: ALTTTFEE → TVEPKREK
     277-479: Missing.
Notes: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Isoform 8 (identifier: Q14790-8)

Also known as: Beta-4;

The sequence of this isoform differs from the canonical sequence as follows:
     184-198: Missing.
     269-276: ALTTTFEE → TVEPKREK
     277-479: Missing.
Isoform 9 (identifier: Q14790-9)

Also known as: 8L;

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MEGGRRARVVIESRRNFFLGAFPTPFPAEHVELGRLGDSETAMVPGKGGADYILLPFKKM

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Propeptide1 – 216216
PRO_0000004628
Chain217 – 374158Caspase-8 subunit p18
PRO_0000004629
Propeptide375 – 38410
PRO_0000004630
Chain385 – 47995Caspase-8 subunit p10
PRO_0000004631

Regions

Domain2 – 8079DED 1
Domain100 – 17778DED 2

Sites

Active site3171
Active site3601

Amino acid modifications

Modified residue1881Phosphoserine By similarity
Modified residue2191Phosphoserine
Modified residue3341Phosphotyrosine

Natural variations

Alternative sequence11M → MEGGRRARVVIESRRNFFLG AFPTPFPAEHVELGRLGDSE TAMVPGKGGADYILLPFKKM in isoform 9.
VSP_000808
Alternative sequence1021R → RFHFCRMSWAEANSQCQTQS VPFWRRVDHLLIR in isoform 4.
VSP_000809
Alternative sequence184 – 26784Missing in isoform 3.
VSP_000813
Alternative sequence184 – 22037ERSSS…DSESQ → DFGQSLPNEKQTSGILSDHQ QSQFCKSTGESAQTSQH in isoform 6.
VSP_000811
Alternative sequence184 – 19815Missing in isoform 2, isoform 4 and isoform 8.
VSP_000810
Alternative sequence199 – 23537GEELC…KPRGY → DFGQSLPNEKQTSGILSDHQ QSQFCKSTGESAQTSQH in isoform 5.
VSP_000814
Alternative sequence221 – 479259Missing in isoform 6.
VSP_000812
Alternative sequence236 – 479244Missing in isoform 5.
VSP_000815
Alternative sequence269 – 2768ALTTTFEE → TVEPKREK in isoform 7 and isoform 8.
VSP_000816
Alternative sequence277 – 479203Missing in isoform 7 and isoform 8.
VSP_000817
Natural variant2191S → T: dbSNP rs35976359.
VAR_025816
Natural variant2481R → W in CASP8D. dbSNP rs17860424.
VAR_014204
Natural variant2851D → H: dbSNP rs1045485.
VAR_020127

Experimental info

Mutagenesis731D → A: Abolishes binding to FLASH. Induces NF-kappa-B activation
Sequence conflict2941E → D in AAD24962. Ref.5
Sequence conflict3311A → P Ref.2 Ref.5
Sequence conflict343 – 3442LK → FG in AAL87631. Ref.8

Secondary structure

1 ............................................... 479
Helix Strand Turn

Details...

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Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Alpha-1) [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 7A5FEAA6B39B582F

FASTA47955,391
        10         20         30         40         50         60 
MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS 

        70         80         90        100        110        120 
FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF 

       130        140        150        160        170        180 
KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE 

       190        200        210        220        230        240 
FSKERSSSLE GSPDEFSNGE ELCGVMTISD SPREQDSESQ TLDKVYQMKS KPRGYCLIIN 

       250        260        270        280        290        300 
NHNFAKAREK VPKLHSIRDR NGTHLDAGAL TTTFEELHFE IKPHDDCTVE QIYEILKIYQ 

       310        320        330        340        350        360 
LMDHSNMDCF ICCILSHGDK GIIYGTDGQE APIYELTSQF TGLKCPSLAG KPKVFFIQAC 

       370        380        390        400        410        420 
QGDNYQKGIP VETDSEEQPY LEMDLSSPQT RYIPDEADFL LGMATVNNCV SYRNPAEGTW 

       430        440        450        460        470 
YIQSLCQSLR ERCPRGDDIL TILTEVNYEV SNKDDKKNMG KQMPQPTFTL RKKLVFPSD

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Isoform 2 (Alpha-2) (MCH5-beta) [UniParc].

Checksum: 7F52F14ADE6A02B6
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46453,768
Isoform 3 (Alpha-3) [UniParc].

Checksum: 2787AE831A2B36EF
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39545,929
Isoform 4 (Alpha-4) [UniParc].

Checksum: 68136650A49159D9
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49657,701
Isoform 5 (Beta-1) [UniParc].

Checksum: 7C9013CEA85A77DE
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23527,484
Isoform 6 (Beta-2) [UniParc].