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Details on Person UniProt:P55212 CASP6
| Class:Id | ReferenceGeneProduct:57028 |
|---|---|
| _chainChangeLog | propeptide:1-23 added on Sat February 7 2015;chain:24-179 added on Sat February 7 2015;propeptide:180-193 added on Sat February 7 2015;chain:194-293 added on Sat February 7 2015 |
| _displayName | UniProt:P55212 CASP6 |
| _timestamp | 2024-11-03 19:55:29 |
| chain | propeptide:1-23 chain:24-179 propeptide:180-193 chain:194-293 |
| checksum | 0738AE4F9791EBD7 |
| comment | FUNCTION Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity (PubMed:19133298, PubMed:22858542, PubMed:27032039, PubMed:28864531, PubMed:30420425, PubMed:32298652, PubMed:8663580). Acts as a non-canonical executioner caspase during apoptosis: localizes in the nucleus and cleaves the nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation (PubMed:11953316, PubMed:17401638, PubMed:8663580, PubMed:9463409). Lamin-A/LMNA cleavage is required for chromatin condensation and nuclear disassembly during apoptotic execution (PubMed:11953316). Acts as a regulator of liver damage by promoting hepatocyte apoptosis: in absence of phosphorylation by AMP-activated protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome c release, thereby participating in nonalcoholic steatohepatitis (PubMed:32029622). Cleaves PARK7/DJ-1 in cells undergoing apoptosis (By similarity). Involved in intrinsic apoptosis by mediating cleavage of RIPK1 (PubMed:22858542). Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP (PubMed:10559921, PubMed:14657026). Cleaves phospholipid scramblase proteins XKR4 and XKR9 (By similarity). In addition to apoptosis, involved in different forms of programmed cell death (PubMed:32298652). Plays an essential role in defense against viruses by acting as a central mediator of the ZBP1-mediated pyroptosis, apoptosis, and necroptosis (PANoptosis), independently of its cysteine protease activity (PubMed:32298652). PANoptosis is a unique inflammatory programmed cell death, which provides a molecular scaffold that allows the interactions and activation of machinery required for inflammasome/pyroptosis, apoptosis and necroptosis (PubMed:32298652). Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death (PubMed:32298652). Plays an essential role in axon degeneration during axon pruning which is the remodeling of axons during neurogenesis but not apoptosis (By similarity). Regulates B-cell programs both during early development and after antigen stimulation (By similarity).FUNCTION (Microbial infection) Proteolytically cleaves the N protein of coronaviruses such as MERS-CoV and SARS-CoV (PubMed:18155731, PubMed:35922005). The cleavage of MERS-CoV N-protein leads to two fragments and modulates coronavirus replication by regulating IFN signaling. The two fragments produced by the cleavage interact with IRF3 inhibiting its nuclear translocation after activation and reduce the expression of IFNB and IFN-stimulated genes (PubMed:35922005). The same mechanism seems to be used by other coronaviruses such as SARS-CoV and SARS-CoV-2 to enhance their replication (PubMed:35922005).CATALYTIC ACTIVITY Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Val-Glu-His-Asp-|-.ACTIVITY REGULATION During activation, the N-terminal disordered prodomain is removed by cleavage (PubMed:19133298, PubMed:28864531, PubMed:8663580, PubMed:8900201). Concomitantly, double cleavage gives rise to a large 18-kDa and a small 11-kDa subunit (PubMed:19133298, PubMed:8663580). The two large and two small subunits then assemble to form the active CASP6 complex (PubMed:8663580). Can be cleaved and activated by different caspases, depending on the context (PubMed:19133298, PubMed:9463409). Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain (PubMed:19133298, PubMed:28864531). Intramolecular cleavage at Asp-193 is a prerequisite for CASP6 self-activation (PubMed:20890311, PubMed:28864531). Cleaved and activated by CASP1 in neurons, possibly in the context of inflammation (PubMed:16123779). Phosphorylation at Ser-257 inhibits autocleavage, preventing caspase activation (PubMed:15273717, PubMed:22433863, PubMed:22483120, PubMed:32029622). Specifically inhibited by compound 3 (benzyloxycarbonyl (Z)-VEID-tetrafluorophenoxymethyl ketone) (PubMed:23227217).SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 11 kDa (p11) subunits (PubMed:19133298, PubMed:19694615, PubMed:20890311). Interacts with BIRC6/bruce (PubMed:15200957). Interacts with RIPK3 (PubMed:32298652).SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.INTERACTION The N-terminal disordered prodomain is required to prevent self-activation.DOMAIN The Tri-arginine exosite is required to recruit substrates for hydrolysis.DOMAIN Undergoes helix-strand structural transitions upon substrate-binding: the 130's region interconverts between an inactive helical state and the canonically active strand state (PubMed:28154009). Other caspases rest constitutively in the strand conformation before and after substrate-binding (PubMed:28154009).PTM Phosphorylated by NUAK1; phosphorylation inhibits self-activation (PubMed:15273717, PubMed:22483120). Phosphorylation at Ser-257 by AMP-activated protein kinase (PRKAA1 or PRKAA2) inhibits autocleavage, preventing caspase activation, thereby preventing hepatocyte apoptosis (PubMed:32029622).PTM Palmitoylation by ZDHHC17 blocks dimerization and subsequent activation, leading to inhibit the cysteine protease activity.PTM Can be cleaved and activated by different caspases, depending on the context (PubMed:19133298, PubMed:28864531). Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain (PubMed:19133298, PubMed:28864531). Cleaved and activated by CASP1, possibly in the context of inflammation (PubMed:16123779).SIMILARITY Belongs to the peptidase C14A family. |
| description | recommendedName: fullName evidence="29"Caspase-6 shortName: CASP-6 shortName evidence="30"CSP-6 ecNumber evidence="10 11 12 21 22"3.4.22.59 alternativeName: fullName evidence="32"Apoptotic protease Mch-2 component recommendedName: fullName evidence="33"Caspase-6 subunit p18 alternativeName: fullName evidence="31"Caspase-6 subunit p20 /component component recommendedName: fullName evidence="33"Caspase-6 subunit p11 alternativeName: fullName evidence="31"Caspase-6 subunit p10 /component |
| geneName | CASP6 MCH2 |
| identifier | P55212 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Alternative splicing Apoptosis Autocatalytic cleavage Cytoplasm Hydrolase Lipoprotein Nucleus Palmitate Phosphoprotein Protease Proteomics identification Reference proteome Thiol protease Zymogen |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 |
| name | CASP6 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:6798130] ENSEMBL:ENSG00000138794 CASP6 [Homo sapiens] |
| secondaryIdentifier | CASP6_HUMAN Q9BQE7 |
| sequenceLength | 293 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:148665] UniProt:P55212-2 CASP6 [Homo sapiens] [ReferenceIsoform:404438] UniProt:P55212-1 CASP6 [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:266128] CASP6(194-293) [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:350313] CASP6(24-179) [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:352246] CASP6(194-293) [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:352247] CASP6(24-179) [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:6798132] CASP6 (1-293) [cytosol] [Homo sapiens] |
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No pathways have been reviewed or authored by UniProt:P55212 CASP6 (57028)
