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
