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CASP6_BOVIN
ID   CASP6_BOVIN             Reviewed;         293 AA.
AC   Q3T0P5;
DT   03-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT   11-OCT-2005, sequence version 1.
DT   25-MAY-2022, entry version 97.
DE   RecName: Full=Caspase-6 {ECO:0000305};
DE            Short=CASP-6;
DE            EC=3.4.22.59 {ECO:0000250|UniProtKB:P55212};
DE   Contains:
DE     RecName: Full=Caspase-6 subunit p18 {ECO:0000250|UniProtKB:P55212};
DE   Contains:
DE     RecName: Full=Caspase-6 subunit p11 {ECO:0000250|UniProtKB:P55212};
DE   Flags: Precursor;
GN   Name=CASP6 {ECO:0000250|UniProtKB:P55212};
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Crossbred X Angus; TISSUE=Ileum;
RG   NIH - Mammalian Gene Collection (MGC) project;
RL   Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Cysteine protease that plays essential roles in programmed
CC       cell death, axonal degeneration, development and innate immunity (By
CC       similarity). Acts as a non-canonical executioner caspase during
CC       apoptosis: localizes in the nucleus and cleaves the nuclear structural
CC       protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and
CC       fragmentation. Lamin-A/LMNA cleavage is required for chromatin
CC       condensation and nuclear disassembly during apoptotic execution (By
CC       similarity). Acts as a regulator of liver damage by promoting
CC       hepatocyte apoptosis: in absence of phosphorylation by AMP-activated
CC       protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome
CC       c release, thereby participating in nonalcoholic steatohepatitis.
CC       Cleaves PARK7/DJ-1 in cells undergoing apoptosis (By similarity).
CC       Involved in intrinsic apoptosis by mediating cleavage of RIPK1.
CC       Furthermore, cleaves many transcription factors such as NF-kappa-B and
CC       cAMP response element-binding protein/CREBBP (By similarity). Cleaves
CC       phospholipid scramblase proteins XKR4 and XKR9. In addition to
CC       apoptosis, involved in different forms of programmed cell death. Plays
CC       an essential role in defense against viruses by acting as a central
CC       mediator of the ZBP1-mediated pyroptosis, apoptosis, and necroptosis
CC       (PANoptosis), independently of its cysteine protease activity.
CC       PANoptosis is a unique inflammatory programmed cell death, which
CC       provides a molecular scaffold that allows the interactions and
CC       activation of machinery required for inflammasome/pyroptosis, apoptosis
CC       and necroptosis. Mechanistically, interacts with RIPK3 and enhances the
CC       interaction between RIPK3 and ZBP1, leading to ZBP1-mediated
CC       inflammasome activation and cell death. Plays an essential role in axon
CC       degeneration during axon pruning which is the remodeling of axons
CC       during neurogenesis but not apoptosis. Regulates B-cell programs both
CC       during early development and after antigen stimulation (By similarity).
CC       {ECO:0000250|UniProtKB:O08738, ECO:0000250|UniProtKB:P55212}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Strict requirement for Asp at position P1 and has a preferred
CC         cleavage sequence of Val-Glu-His-Asp-|-.; EC=3.4.22.59;
CC         Evidence={ECO:0000250|UniProtKB:P55212};
CC   -!- ACTIVITY REGULATION: During activation, the N-terminal disordered
CC       prodomain is removed by cleavage. Concomitantly, double cleavage gives
CC       rise to a large 18-kDa and a small 11-kDa subunit. The two large and
CC       two small subunits then assemble to form the active CASP6 complex. Can
CC       be cleaved and activated by different caspases, depending on the
CC       context. Cleaved and activated by caspase-8 (CASP8) and subsequently by
CC       caspase-3 (CASP3). Can also undergo autoactivation by mediating
CC       autocleavage at Asp-179 and Asp-193, while it is not able to cleave its
CC       N-terminal disordered prodomain. Intramolecular cleavage at Asp-193 is
CC       a prerequisite for CASP6 self-activation. Cleaved and activated by
CC       CASP1 in neurons, possibly in the context of inflammation.
CC       Phosphorylation at Ser-257 inhibits autocleavage, preventing caspase
CC       activation. {ECO:0000250|UniProtKB:P55212}.
CC   -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged
CC       heterodimers, each one formed by a 18 kDa (p18) and a 11 kDa (p11)
CC       subunits. Interacts with BIRC6/bruce. Interacts with RIPK3.
CC       {ECO:0000250|UniProtKB:P55212}.
CC   -!- SUBUNIT: [Caspase-6 subunit p18]: Heterotetramer that consists of two
CC       anti-parallel arranged heterodimers, each one formed by a 18 kDa
CC       (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.
CC       {ECO:0000250|UniProtKB:P55212}.
CC   -!- SUBUNIT: [Caspase-6 subunit p11]: Heterotetramer that consists of two
CC       anti-parallel arranged heterodimers, each one formed by a 18 kDa
CC       (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.
CC       {ECO:0000250|UniProtKB:P55212}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P55212}. Nucleus
CC       {ECO:0000250|UniProtKB:P55212}.
CC   -!- DOMAIN: The N-terminal disordered prodomain is required to prevent
CC       self-activation. {ECO:0000250|UniProtKB:P55212}.
CC   -!- DOMAIN: The Tri-arginine exosite is required to recruit substrates for
CC       hydrolysis. {ECO:0000250|UniProtKB:P55212}.
CC   -!- DOMAIN: Undergoes helix-strand structural transitions upon substrate-
CC       binding: the 130's region interconverts between an inactive helical
CC       state and the canonically active strand state. Other caspases rest
CC       constitutively in the strand conformation before and after substrate-
CC       binding. {ECO:0000250|UniProtKB:P55212}.
CC   -!- PTM: Phosphorylated by NUAK1; phosphorylation inhibits self-activation.
CC       Phosphorylation at Ser-257 by AMP-activated protein kinase (PRKAA1 or
CC       PRKAA2) inhibits autocleavage, preventing caspase activation, thereby
CC       preventing hepatocyte apoptosis. {ECO:0000250|UniProtKB:P55212}.
CC   -!- PTM: Palmitoylation by ZDHHC17 blocks dimerization and subsequent
CC       activation, leading to inhibit the cysteine protease activity.
CC       {ECO:0000250|UniProtKB:P55212}.
CC   -!- PTM: Can be cleaved and activated by different caspases, depending on
CC       the context. Cleaved and activated by caspase-8 (CASP8) and
CC       subsequently by caspase-3 (CASP3). Can also undergo autoactivation by
CC       mediating autocleavage at Asp-179 and Asp-193, while it is not able to
CC       cleave its N-terminal disordered prodomain. Cleaved and activated by
CC       CASP1, possibly in the context of inflammation.
CC       {ECO:0000250|UniProtKB:P55212}.
CC   -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
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DR   EMBL; BC102309; AAI02310.1; -; mRNA.
DR   RefSeq; NP_001030496.1; NM_001035419.2.
DR   AlphaFoldDB; Q3T0P5; -.
DR   SMR; Q3T0P5; -.
DR   STRING; 9913.ENSBTAP00000016642; -.
DR   MEROPS; C14.005; -.
DR   PaxDb; Q3T0P5; -.
DR   PRIDE; Q3T0P5; -.
DR   GeneID; 538409; -.
DR   KEGG; bta:538409; -.
DR   CTD; 839; -.
DR   eggNOG; KOG3573; Eukaryota.
DR   InParanoid; Q3T0P5; -.
DR   OrthoDB; 984395at2759; -.
DR   Proteomes; UP000009136; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0004197; F:cysteine-type endopeptidase activity; ISS:UniProtKB.
DR   GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR   GO; GO:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; IBA:GO_Central.
DR   GO; GO:0002218; P:activation of innate immune response; ISS:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IBA:GO_Central.
DR   GO; GO:0097284; P:hepatocyte apoptotic process; ISS:UniProtKB.
DR   GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; ISS:UniProtKB.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0060545; P:positive regulation of necroptotic process; ISS:UniProtKB.
DR   GO; GO:0016540; P:protein autoprocessing; ISS:UniProtKB.
DR   GO; GO:0070269; P:pyroptosis; ISS:UniProtKB.
DR   CDD; cd00032; CASc; 1.
DR   InterPro; IPR029030; Caspase-like_dom_sf.
DR   InterPro; IPR037554; Caspase_6.
DR   InterPro; IPR033139; Caspase_cys_AS.
DR   InterPro; IPR016129; Caspase_his_AS.
DR   InterPro; IPR002398; Pept_C14.
DR   InterPro; IPR002138; Pept_C14_p10.
DR   InterPro; IPR001309; Pept_C14_p20.
DR   InterPro; IPR015917; Pept_C14A.
DR   PANTHER; PTHR10454; PTHR10454; 1.
DR   PANTHER; PTHR10454:SF206; PTHR10454:SF206; 1.
DR   PRINTS; PR00376; IL1BCENZYME.
DR   SMART; SM00115; CASc; 1.
DR   SUPFAM; SSF52129; SSF52129; 1.
DR   PROSITE; PS01122; CASPASE_CYS; 1.
DR   PROSITE; PS01121; CASPASE_HIS; 1.
DR   PROSITE; PS50207; CASPASE_P10; 1.
DR   PROSITE; PS50208; CASPASE_P20; 1.
PE   2: Evidence at transcript level;
KW   Apoptosis; Autocatalytic cleavage; Cytoplasm; Hydrolase; Lipoprotein;
KW   Nucleus; Palmitate; Phosphoprotein; Protease; Reference proteome;
KW   Thiol protease; Zymogen.
FT   PROPEP          1..23
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT                   /id="PRO_0000282876"
FT   CHAIN           24..179
FT                   /note="Caspase-6 subunit p18"
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT                   /id="PRO_0000282877"
FT   PROPEP          180..193
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT                   /id="PRO_0000282878"
FT   CHAIN           194..293
FT                   /note="Caspase-6 subunit p11"
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT                   /id="PRO_0000282879"
FT   REGION          1..20
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          42..44
FT                   /note="Tri-arginine exosite"
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT   REGION          125..142
FT                   /note="130's region"
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT   ACT_SITE        121
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT   ACT_SITE        163
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT   MOD_RES         79
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O08738"
FT   MOD_RES         257
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT   LIPID           264
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
FT   LIPID           277
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000250|UniProtKB:P55212"
SQ   SEQUENCE   293 AA;  33350 MW;  AC47609E52B0F00F CRC64;
     MSSEPPPRRA RGPGEEQNMT EIDAFPRREI FDPTEKYKMD HKRRGIALIF NHERFFWHLT
     LPNRPGTSAD RDNLRRRFSD LGFEVKCFDD LRAEELLLKI HEASTASHVD ADCFLCVFLS
     HGEGNHIYAY DAKIEIQTLT GLFKGDKCQS LVGKPKIFII QACRGSQHDV PVIPLDVVDH
     RTDTPDANLT QVDAASVYTL PAGADFLMCY SVAEGYYSHR ETVNGSWYIQ DLCEMLGKFG
     SSLEFTELLT LVNRKVSQRR VDFCRDPNAI GKKQVPCFAS MLTKKLHFSP KSK
 
 
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