CASP6_HUMAN
ID CASP6_HUMAN Reviewed; 293 AA.
AC P55212; Q9BQE7;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2002, sequence version 2.
DT 03-AUG-2022, entry version 220.
DE RecName: Full=Caspase-6 {ECO:0000303|PubMed:11953316};
DE Short=CASP-6;
DE Short=CSP-6 {ECO:0000303|PubMed:16123779};
DE EC=3.4.22.59 {ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:19694615, ECO:0000269|PubMed:20890311, ECO:0000269|PubMed:30420425, ECO:0000269|PubMed:32029622};
DE AltName: Full=Apoptotic protease Mch-2 {ECO:0000303|PubMed:7796396};
DE Contains:
DE RecName: Full=Caspase-6 subunit p18 {ECO:0000303|PubMed:8900201};
DE AltName: Full=Caspase-6 subunit p20 {ECO:0000303|PubMed:19133298};
DE Contains:
DE RecName: Full=Caspase-6 subunit p11 {ECO:0000303|PubMed:8900201};
DE AltName: Full=Caspase-6 subunit p10 {ECO:0000303|PubMed:19133298};
DE Flags: Precursor;
GN Name=CASP6 {ECO:0000312|HGNC:HGNC:1507};
GN Synonyms=MCH2 {ECO:0000303|PubMed:7796396};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA AND BETA).
RC TISSUE=T-cell;
RX PubMed=7796396;
RA Fernandes-Alnemri T., Litwack G., Alnemri E.S.;
RT "Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene
RT family.";
RL Cancer Res. 55:2737-2742(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT SER-182.
RG NIEHS SNPs program;
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PROTEOLYTIC PROCESSING.
RC TISSUE=Lymphocyte;
RX PubMed=8900201; DOI=10.1074/jbc.271.43.27099;
RA Srinivasula S.M., Fernandes-Alnemri T., Zangrilli J., Robertson N.,
RA Armstrong R.C., Wang L., Trapani J.A., Tomaselli K.J., Litwack G.,
RA Alnemri E.S.;
RT "The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the
RT lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator
RT CPP32.";
RL J. Biol. Chem. 271:27099-27106(1996).
RN [5]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=8663580;
RA Orth K., Chinnaiyan A.M., Garg M., Froelich C.J., Dixit V.M.;
RT "The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves
RT the death substrate lamin A.";
RL J. Biol. Chem. 271:16443-16446(1996).
RN [6]
RP FUNCTION, ACTIVITY REGULATION, AND CLEAVAGE BY CASP8 AND CASP3.
RX PubMed=9463409; DOI=10.1084/jem.187.4.587;
RA Hirata H., Takahashi A., Kobayashi S., Yonehara S., Sawai H., Okazaki T.,
RA Yamamoto K., Sasada M.;
RT "Caspases are activated in a branched protease cascade and control distinct
RT downstream processes in Fas-induced apoptosis.";
RL J. Exp. Med. 187:587-600(1998).
RN [7]
RP FUNCTION.
RX PubMed=10559921; DOI=10.1038/12050;
RA Levkau B., Scatena M., Giachelli C.M., Ross R., Raines E.W.;
RT "Apoptosis overrides survival signals through a caspase-mediated dominant-
RT negative NF-kappa B loop.";
RL Nat. Cell Biol. 1:227-233(1999).
RN [8]
RP FUNCTION.
RX PubMed=11953316; DOI=10.1093/emboj/21.8.1967;
RA Ruchaud S., Korfali N., Villa P., Kottke T.J., Dingwall C., Kaufmann S.H.,
RA Earnshaw W.C.;
RT "Caspase-6 gene disruption reveals a requirement for lamin A cleavage in
RT apoptotic chromatin condensation.";
RL EMBO J. 21:1967-1977(2002).
RN [9]
RP FUNCTION.
RX PubMed=14657026; DOI=10.1093/emboj/cdg615;
RA Rouaux C., Jokic N., Mbebi C., Boutillier S., Loeffler J.P.,
RA Boutillier A.L.;
RT "Critical loss of CBP/p300 histone acetylase activity by caspase-6 during
RT neurodegeneration.";
RL EMBO J. 22:6537-6549(2003).
RN [10]
RP INTERACTION WITH BIRC6/BRUCE.
RX PubMed=15200957; DOI=10.1016/j.molcel.2004.05.018;
RA Bartke T., Pohl C., Pyrowolakis G., Jentsch S.;
RT "Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin
RT ligase.";
RL Mol. Cell 14:801-811(2004).
RN [11]
RP ACTIVITY REGULATION, PHOSPHORYLATION AT SER-257, AND MUTAGENESIS OF
RP SER-257.
RX PubMed=15273717; DOI=10.1038/sj.onc.1207963;
RA Suzuki A., Kusakai G., Kishimoto A., Shimojo Y., Miyamoto S., Ogura T.,
RA Ochiai A., Esumi H.;
RT "Regulation of caspase-6 and FLIP by the AMPK family member ARK5.";
RL Oncogene 23:7067-7075(2004).
RN [12]
RP ACTIVITY REGULATION, PROTEOLYTIC PROCESSING, ACTIVE SITE, AND MUTAGENESIS
RP OF CYS-163.
RX PubMed=16123779; DOI=10.1038/sj.cdd.4401753;
RA Guo H., Petrin D., Zhang Y., Bergeron C., Goodyer C.G., LeBlanc A.C.;
RT "Caspase-1 activation of caspase-6 in human apoptotic neurons.";
RL Cell Death Differ. 13:285-292(2006).
RN [13]
RP FUNCTION.
RX PubMed=17401638; DOI=10.1007/s11373-007-9165-3;
RA Lin H.H., Hsu H.L., Yeh N.H.;
RT "Apoptotic cleavage of NuMA at the C-terminal end is related to nuclear
RT disruption and death amplification.";
RL J. Biomed. Sci. 14:681-694(2007).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PROTEOLYTIC PROCESSING,
RP SUBUNIT, DOMAIN, ACTIVE SITE, AND MUTAGENESIS OF ASP-23; CYS-163; ASP-179
RP AND ASP-193.
RX PubMed=19133298; DOI=10.1016/j.bbamcr.2008.12.004;
RA Klaiman G., Champagne N., LeBlanc A.C.;
RT "Self-activation of Caspase-6 in vitro and in vivo: Caspase-6 activation
RT does not induce cell death in HEK293T cells.";
RL Biochim. Biophys. Acta 1793:592-601(2009).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [16]
RP FUNCTION.
RX PubMed=22858542; DOI=10.1038/cdd.2012.98;
RA van Raam B.J., Ehrnhoefer D.E., Hayden M.R., Salvesen G.S.;
RT "Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-
RT 6.";
RL Cell Death Differ. 20:86-96(2013).
RN [17]
RP PALMITOYLATION AT CYS-264 AND CYS-277, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF CYS-264 AND CYS-277.
RX PubMed=27911442; DOI=10.1038/cdd.2016.139;
RA Skotte N.H., Sanders S.S., Singaraja R.R., Ehrnhoefer D.E., Vaid K.,
RA Qiu X., Kannan S., Verma C., Hayden M.R.;
RT "Palmitoylation of caspase-6 by HIP14 regulates its activation.";
RL Cell Death Differ. 24:433-444(2017).
RN [18]
RP DOMAIN, AND MUTAGENESIS OF GLU-135.
RX PubMed=28154009; DOI=10.1074/jbc.m116.773499;
RA Dagbay K.B., Bolik-Coulon N., Savinov S.N., Hardy J.A.;
RT "Caspase-6 undergoes a distinct helix-strand interconversion upon substrate
RT binding.";
RL J. Biol. Chem. 292:4885-4897(2017).
RN [19]
RP FUNCTION, ACTIVITY REGULATION, PROTEOLYTIC PROCESSING, ACTIVE SITE, AND
RP MUTAGENESIS OF ASP-23; CYS-163; ASP-179 AND ASP-193.
RX PubMed=28864531; DOI=10.1073/pnas.1704640114;
RA Dagbay K.B., Hardy J.A.;
RT "Multiple proteolytic events in caspase-6 self-activation impact
RT conformations of discrete structural regions.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:E7977-E7986(2017).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITES, AND MUTAGENESIS OF
RP 42-ARG--ARG-44; HIS-121 AND CYS-163.
RX PubMed=30420425; DOI=10.1074/jbc.ra118.005914;
RA MacPherson D.J., Mills C.L., Ondrechen M.J., Hardy J.A.;
RT "Tri-arginine exosite patch of caspase-6 recruits substrates for
RT hydrolysis.";
RL J. Biol. Chem. 294:71-88(2019).
RN [21]
RP FUNCTION, AND INTERACTION WITH RIPK3.
RX PubMed=32298652; DOI=10.1016/j.cell.2020.03.040;
RA Zheng M., Karki R., Vogel P., Kanneganti T.D.;
RT "Caspase-6 is a key regulator of innate immunity, inflammasome activation,
RT and host defense.";
RL Cell 181:674-687(2020).
RN [22]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PHOSPHORYLATION AT
RP SER-257, AND MUTAGENESIS OF SER-257.
RX PubMed=32029622; DOI=10.1126/science.aay0542;
RA Zhao P., Sun X., Chaggan C., Liao Z., In Wong K., He F., Singh S.,
RA Loomba R., Karin M., Witztum J.L., Saltiel A.R.;
RT "An AMPK-caspase-6 axis controls liver damage in nonalcoholic
RT steatohepatitis.";
RL Science 367:652-660(2020).
RN [23] {ECO:0007744|PDB:2WDP}
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS), CATALYTIC ACTIVITY, SUBUNIT, ACTIVE
RP SITE, AND MUTAGENESIS OF CYS-163.
RX PubMed=19694615; DOI=10.1042/bj20090540;
RA Baumgartner R., Meder G., Briand C., Decock A., D'arcy A., Hassiepen U.,
RA Morse R., Renatus M.;
RT "The crystal structure of caspase-6, a selective effector of axonal
RT degeneration.";
RL Biochem. J. 423:429-439(2009).
RN [24] {ECO:0007744|PDB:3NR2, ECO:0007744|PDB:3OD5}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 24-293, CATALYTIC ACTIVITY,
RP ACTIVE SITE, SUBUNIT, ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-163.
RX PubMed=20890311; DOI=10.1038/embor.2010.141;
RA Wang X.J., Cao Q., Liu X., Wang K.T., Mi W., Zhang Y., Li L.F.,
RA LeBlanc A.C., Su X.D.;
RT "Crystal structures of human caspase 6 reveal a new mechanism for
RT intramolecular cleavage self-activation.";
RL EMBO Rep. 11:841-847(2010).
RN [25] {ECO:0007744|PDB:3V6L, ECO:0007744|PDB:3V6M}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 21-293, ACTIVITY REGULATION, AND
RP MUTAGENESIS OF SER-257.
RX PubMed=22433863; DOI=10.1074/jbc.m112.351213;
RA Cao Q., Wang X.J., Liu C.W., Liu D.F., Li L.F., Gao Y.Q., Su X.D.;
RT "Inhibitory mechanism of caspase-6 phosphorylation revealed by crystal
RT structures, molecular dynamics simulations, and biochemical assays.";
RL J. Biol. Chem. 287:15371-15379(2012).
RN [26] {ECO:0007744|PDB:4HVA}
RP X-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS) OF 24-293, AND ACTIVITY REGULATION.
RX PubMed=23227217; DOI=10.1371/journal.pone.0050864;
RA Heise C.E., Murray J., Augustyn K.E., Bravo B., Chugha P., Cohen F.,
RA Giannetti A.M., Gibbons P., Hannoush R.N., Hearn B.R., Jaishankar P.,
RA Ly C.Q., Shah K., Stanger K., Steffek M., Tang Y., Zhao X., Lewcock J.W.,
RA Renslo A.R., Flygare J., Arkin M.R.;
RT "Mechanistic and structural understanding of uncompetitive inhibitors of
RT caspase-6.";
RL PLoS ONE 7:e50864-e50864(2012).
RN [27] {ECO:0007744|PDB:3S8E}
RP X-RAY CRYSTALLOGRAPHY (2.88 ANGSTROMS) OF 24-293, PHOSPHORYLATION AT
RP SER-257, MUTAGENESIS OF SER-257, AND ACTIVITY REGULATION.
RX PubMed=22483120; DOI=10.1016/j.str.2012.02.003;
RA Velazquez-Delgado E.M., Hardy J.A.;
RT "Phosphorylation regulates assembly of the caspase-6 substrate-binding
RT groove.";
RL Structure 20:742-751(2012).
CC -!- FUNCTION: Cysteine protease that plays essential roles in programmed
CC cell death, axonal degeneration, development and innate immunity
CC (PubMed:8663580, PubMed:19133298, PubMed:22858542, PubMed:28864531,
CC PubMed:30420425, PubMed:32298652). Acts as a non-canonical executioner
CC caspase during apoptosis: localizes in the nucleus and cleaves the
CC nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing
CC nuclear shrinkage and fragmentation (PubMed:8663580, PubMed:9463409,
CC PubMed:11953316, PubMed:17401638). Lamin-A/LMNA cleavage is required
CC for chromatin condensation and nuclear disassembly during apoptotic
CC execution (PubMed:11953316). Acts as a regulator of liver damage by
CC promoting hepatocyte apoptosis: in absence of phosphorylation by AMP-
CC activated protein kinase (AMPK), catalyzes cleavage of BID, leading to
CC cytochrome c release, thereby participating in nonalcoholic
CC steatohepatitis (PubMed:32029622). Cleaves PARK7/DJ-1 in cells
CC undergoing apoptosis (By similarity). Involved in intrinsic apoptosis
CC by mediating cleavage of RIPK1 (PubMed:22858542). Furthermore, cleaves
CC many transcription factors such as NF-kappa-B and cAMP response
CC element-binding protein/CREBBP (PubMed:10559921, PubMed:14657026).
CC Cleaves phospholipid scramblase proteins XKR4 and XKR9 (By similarity).
CC In addition to apoptosis, involved in different forms of programmed
CC cell death (PubMed:32298652). Plays an essential role in defense
CC against viruses by acting as a central mediator of the ZBP1-mediated
CC pyroptosis, apoptosis, and necroptosis (PANoptosis), independently of
CC its cysteine protease activity (PubMed:32298652). PANoptosis is a
CC unique inflammatory programmed cell death, which provides a molecular
CC scaffold that allows the interactions and activation of machinery
CC required for inflammasome/pyroptosis, apoptosis and necroptosis
CC (PubMed:32298652). Mechanistically, interacts with RIPK3 and enhances
CC the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated
CC inflammasome activation and cell death (PubMed:32298652). Plays an
CC essential role in axon degeneration during axon pruning which is the
CC remodeling of axons during neurogenesis but not apoptosis (By
CC similarity). Regulates B-cell programs both during early development
CC and after antigen stimulation (By similarity).
CC {ECO:0000250|UniProtKB:O08738, ECO:0000269|PubMed:10559921,
CC ECO:0000269|PubMed:11953316, ECO:0000269|PubMed:14657026,
CC ECO:0000269|PubMed:17401638, ECO:0000269|PubMed:19133298,
CC ECO:0000269|PubMed:22858542, ECO:0000269|PubMed:28864531,
CC ECO:0000269|PubMed:30420425, ECO:0000269|PubMed:32029622,
CC ECO:0000269|PubMed:32298652, ECO:0000269|PubMed:8663580,
CC ECO:0000269|PubMed:9463409}.
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:0000269|PubMed:19133298, ECO:0000269|PubMed:19694615,
CC ECO:0000269|PubMed:30420425, ECO:0000269|PubMed:32029622};
CC -!- ACTIVITY REGULATION: During activation, the N-terminal disordered
CC prodomain is removed by cleavage (PubMed:8900201, PubMed:8663580,
CC PubMed:19133298, PubMed:28864531). Concomitantly, double cleavage gives
CC rise to a large 18-kDa and a small 11-kDa subunit (PubMed:8663580,
CC PubMed:19133298). The two large and two small subunits then assemble to
CC form the active CASP6 complex (PubMed:8663580). Can be cleaved and
CC activated by different caspases, depending on the context
CC (PubMed:9463409, PubMed:19133298). Cleaved and activated by caspase-8
CC (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can
CC also undergo autoactivation by mediating autocleavage at Asp-179 and
CC Asp-193, while it is not able to cleave its N-terminal disordered
CC prodomain (PubMed:19133298, PubMed:28864531). Intramolecular cleavage
CC at Asp-193 is a prerequisite for CASP6 self-activation
CC (PubMed:20890311, PubMed:28864531). Cleaved and activated by CASP1 in
CC neurons, possibly in the context of inflammation (PubMed:16123779).
CC Phosphorylation at Ser-257 inhibits autocleavage, preventing caspase
CC activation (PubMed:15273717, PubMed:32029622, PubMed:22433863,
CC PubMed:22483120). Specifically inhibited by compound 3
CC (benzyloxycarbonyl (Z)-VEID-tetrafluorophenoxymethyl ketone)
CC (PubMed:23227217). {ECO:0000269|PubMed:15273717,
CC ECO:0000269|PubMed:16123779, ECO:0000269|PubMed:19133298,
CC ECO:0000269|PubMed:20890311, ECO:0000269|PubMed:22433863,
CC ECO:0000269|PubMed:22483120, ECO:0000269|PubMed:23227217,
CC ECO:0000269|PubMed:28864531, ECO:0000269|PubMed:32029622,
CC ECO:0000269|PubMed:8663580, ECO:0000269|PubMed:8900201,
CC ECO:0000269|PubMed:9463409}.
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 (PubMed:19133298, PubMed:19694615, PubMed:20890311). Interacts
CC with BIRC6/bruce (PubMed:15200957). Interacts with RIPK3
CC (PubMed:32298652). {ECO:0000269|PubMed:15200957,
CC ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:19694615,
CC ECO:0000269|PubMed:20890311, ECO:0000269|PubMed:32298652}.
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:0000269|PubMed:19694615, ECO:0000269|PubMed:20890311}.
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:0000269|PubMed:19694615, ECO:0000269|PubMed:20890311}.
CC -!- INTERACTION:
CC P55212; Q9Y614: ACTL7B; NbExp=3; IntAct=EBI-718729, EBI-25835070;
CC P55212; Q6DHV7-2: ADAL; NbExp=3; IntAct=EBI-718729, EBI-18899653;
CC P55212; Q6UY14-3: ADAMTSL4; NbExp=3; IntAct=EBI-718729, EBI-10173507;
CC P55212; Q96MA6: AK8; NbExp=3; IntAct=EBI-718729, EBI-8466265;
CC P55212; Q5T2L2: AKR1C8P; NbExp=3; IntAct=EBI-718729, EBI-22006248;
CC P55212; Q96Q83-2: ALKBH3; NbExp=3; IntAct=EBI-718729, EBI-9089544;
CC P55212; Q9Y303-2: AMDHD2; NbExp=3; IntAct=EBI-718729, EBI-12323557;
CC P55212; Q9NU02: ANKEF1; NbExp=3; IntAct=EBI-718729, EBI-8464238;
CC P55212; Q6LES2: ANXA4; NbExp=3; IntAct=EBI-718729, EBI-10250835;
CC P55212; P06727: APOA4; NbExp=3; IntAct=EBI-718729, EBI-1222447;
CC P55212; Q8WW27: APOBEC4; NbExp=3; IntAct=EBI-718729, EBI-25836284;
CC P55212; Q66PJ3-4: ARL6IP4; NbExp=3; IntAct=EBI-718729, EBI-5280499;
CC P55212; Q6XD76: ASCL4; NbExp=3; IntAct=EBI-718729, EBI-10254793;
CC P55212; P18848: ATF4; NbExp=3; IntAct=EBI-718729, EBI-492498;
CC P55212; Q9H0Y0: ATG10; NbExp=3; IntAct=EBI-718729, EBI-1048913;
CC P55212; Q14032: BAAT; NbExp=3; IntAct=EBI-718729, EBI-8994378;
CC P55212; P54687-4: BCAT1; NbExp=3; IntAct=EBI-718729, EBI-25834445;
CC P55212; P06276: BCHE; NbExp=3; IntAct=EBI-718729, EBI-7936069;
CC P55212; Q9NSI6-4: BRWD1; NbExp=3; IntAct=EBI-718729, EBI-10693038;
CC P55212; Q96Q07-2: BTBD9; NbExp=3; IntAct=EBI-718729, EBI-22006737;
CC P55212; Q9H0W9-3: C11orf54; NbExp=3; IntAct=EBI-718729, EBI-12108466;
CC P55212; Q9NQ89: C12orf4; NbExp=3; IntAct=EBI-718729, EBI-11090973;
CC P55212; Q13901: C1D; NbExp=3; IntAct=EBI-718729, EBI-3844053;
CC P55212; Q3SXR2: C3orf36; NbExp=3; IntAct=EBI-718729, EBI-18036948;
CC P55212; Q8N1A6: C4orf33; NbExp=3; IntAct=EBI-718729, EBI-10264911;
CC P55212; P17655: CAPN2; NbExp=3; IntAct=EBI-718729, EBI-1028956;
CC P55212; P20807-4: CAPN3; NbExp=3; IntAct=EBI-718729, EBI-11532021;
CC P55212; P42574: CASP3; NbExp=2; IntAct=EBI-718729, EBI-524064;
CC P55212; P55212: CASP6; NbExp=8; IntAct=EBI-718729, EBI-718729;
CC P55212; Q5JTY5: CBWD3; NbExp=3; IntAct=EBI-718729, EBI-723434;
CC P55212; O00257-3: CBX4; NbExp=3; IntAct=EBI-718729, EBI-4392727;
CC P55212; P24863: CCNC; NbExp=3; IntAct=EBI-718729, EBI-395261;
CC P55212; Q9NNX6-10: CD209; NbExp=3; IntAct=EBI-718729, EBI-12300031;
CC P55212; Q9UJX2: CDC23; NbExp=3; IntAct=EBI-718729, EBI-396137;
CC P55212; P42773: CDKN2C; NbExp=3; IntAct=EBI-718729, EBI-711290;
CC P55212; O95674: CDS2; NbExp=3; IntAct=EBI-718729, EBI-3913685;
CC P55212; Q494V2-2: CFAP100; NbExp=3; IntAct=EBI-718729, EBI-11953200;
CC P55212; Q8WUX9: CHMP7; NbExp=3; IntAct=EBI-718729, EBI-749253;
CC P55212; Q9Y3D0: CIAO2B; NbExp=3; IntAct=EBI-718729, EBI-744045;
CC P55212; Q8N365: CIART; NbExp=3; IntAct=EBI-718729, EBI-10265133;
CC P55212; Q99966: CITED1; NbExp=3; IntAct=EBI-718729, EBI-2624951;
CC P55212; P09496-2: CLTA; NbExp=3; IntAct=EBI-718729, EBI-4401010;
CC P55212; Q6PJW8-3: CNST; NbExp=3; IntAct=EBI-718729, EBI-25836090;
CC P55212; Q96BR5: COA7; NbExp=3; IntAct=EBI-718729, EBI-6269632;
CC P55212; P02458-1: COL2A1; NbExp=3; IntAct=EBI-718729, EBI-12375799;
CC P55212; Q9UGL9: CRCT1; NbExp=3; IntAct=EBI-718729, EBI-713677;
CC P55212; Q9UKG9-2: CROT; NbExp=3; IntAct=EBI-718729, EBI-25835363;
CC P55212; P26998: CRYBB3; NbExp=3; IntAct=EBI-718729, EBI-1965681;
CC P55212; P35222: CTNNB1; NbExp=3; IntAct=EBI-718729, EBI-491549;
CC P55212; Q53TN4: CYBRD1; NbExp=3; IntAct=EBI-718729, EBI-8637742;
CC P55212; P61962: DCAF7; NbExp=3; IntAct=EBI-718729, EBI-359808;
CC P55212; O60479: DLX3; NbExp=3; IntAct=EBI-718729, EBI-3908248;
CC P55212; Q96EY1-3: DNAJA3; NbExp=3; IntAct=EBI-718729, EBI-11526226;
CC P55212; Q92782-2: DPF1; NbExp=3; IntAct=EBI-718729, EBI-23669343;
CC P55212; Q9BPU6: DPYSL5; NbExp=3; IntAct=EBI-718729, EBI-724653;
CC P55212; A0AVK6: E2F8; NbExp=3; IntAct=EBI-718729, EBI-7779316;
CC P55212; Q658K8: EEF1DP3; NbExp=3; IntAct=EBI-718729, EBI-10248874;
CC P55212; O00303: EIF3F; NbExp=3; IntAct=EBI-718729, EBI-711990;
CC P55212; Q13347: EIF3I; NbExp=3; IntAct=EBI-718729, EBI-354047;
CC P55212; O00472: ELL2; NbExp=3; IntAct=EBI-718729, EBI-395274;
CC P55212; O00423: EML1; NbExp=3; IntAct=EBI-718729, EBI-751327;
CC P55212; Q6NXG1-3: ESRP1; NbExp=3; IntAct=EBI-718729, EBI-21567429;
CC P55212; Q49AJ0-4: FAM135B; NbExp=3; IntAct=EBI-718729, EBI-25835236;
CC P55212; Q8N128-2: FAM177A1; NbExp=3; IntAct=EBI-718729, EBI-12201693;
CC P55212; Q8IZU1: FAM9A; NbExp=3; IntAct=EBI-718729, EBI-8468186;
CC P55212; Q6ZNL6: FGD5; NbExp=3; IntAct=EBI-718729, EBI-7962481;
CC P55212; Q9NSA1: FGF21; NbExp=3; IntAct=EBI-718729, EBI-3909329;
CC P55212; Q06547-3: GABPB1; NbExp=3; IntAct=EBI-718729, EBI-9088619;
CC P55212; Q49A26-4: GLYR1; NbExp=3; IntAct=EBI-718729, EBI-12143817;
CC P55212; Q9HAV0: GNB4; NbExp=3; IntAct=EBI-718729, EBI-358539;
CC P55212; Q6NXT2: H3-5; NbExp=3; IntAct=EBI-718729, EBI-2868501;
CC P55212; Q9BT25: HAUS8; NbExp=3; IntAct=EBI-718729, EBI-2558143;
CC P55212; Q9NRZ9-6: HELLS; NbExp=3; IntAct=EBI-718729, EBI-12003732;
CC P55212; Q96EW2-2: HSPBAP1; NbExp=3; IntAct=EBI-718729, EBI-25835621;
CC P55212; P42858: HTT; NbExp=15; IntAct=EBI-718729, EBI-466029;
CC P55212; Q8N6M8-2: IQCF1; NbExp=3; IntAct=EBI-718729, EBI-21771049;
CC P55212; Q92613: JADE3; NbExp=3; IntAct=EBI-718729, EBI-10278909;
CC P55212; P0C870: JMJD7; NbExp=3; IntAct=EBI-718729, EBI-9090173;
CC P55212; Q9UK76: JPT1; NbExp=3; IntAct=EBI-718729, EBI-720411;
CC P55212; Q8N5Z5: KCTD17; NbExp=3; IntAct=EBI-718729, EBI-743960;
CC P55212; Q8TBB5-2: KLHDC4; NbExp=3; IntAct=EBI-718729, EBI-21838933;
CC P55212; Q9UH77: KLHL3; NbExp=3; IntAct=EBI-718729, EBI-8524663;
CC P55212; Q8N4N3-2: KLHL36; NbExp=3; IntAct=EBI-718729, EBI-10973851;
CC P55212; Q5JUW0-3: KRBOX4; NbExp=3; IntAct=EBI-718729, EBI-12893625;
CC P55212; Q8N1A0: KRT222; NbExp=3; IntAct=EBI-718729, EBI-8473062;
CC P55212; P13473-2: LAMP2; NbExp=3; IntAct=EBI-718729, EBI-21591415;
CC P55212; Q6DKI2: LGALS9C; NbExp=3; IntAct=EBI-718729, EBI-9088829;
CC P55212; Q9H2C1: LHX5; NbExp=3; IntAct=EBI-718729, EBI-25835523;
CC P55212; Q8N0U6: LINC00518; NbExp=3; IntAct=EBI-718729, EBI-10264791;
CC P55212; Q9Y234: LIPT1; NbExp=3; IntAct=EBI-718729, EBI-727376;
CC P55212; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-718729, EBI-739832;
CC P55212; Q1L5Z9: LONRF2; NbExp=3; IntAct=EBI-718729, EBI-2510853;
CC P55212; Q96JB6: LOXL4; NbExp=3; IntAct=EBI-718729, EBI-749562;
CC P55212; Q16609: LPAL2; NbExp=3; IntAct=EBI-718729, EBI-10238012;
CC P55212; Q8IYG6: LRRC56; NbExp=3; IntAct=EBI-718729, EBI-14752528;
CC P55212; P0DP58-2: LYNX1; NbExp=3; IntAct=EBI-718729, EBI-21916939;
CC P55212; Q969L2: MAL2; NbExp=3; IntAct=EBI-718729, EBI-944295;
CC P55212; P27338: MAOB; NbExp=3; IntAct=EBI-718729, EBI-3911344;
CC P55212; A6NJ78-4: METTL15; NbExp=3; IntAct=EBI-718729, EBI-10174029;
CC P55212; Q96C03-3: MIEF2; NbExp=3; IntAct=EBI-718729, EBI-11988931;
CC P55212; Q8N5J2-3: MINDY1; NbExp=3; IntAct=EBI-718729, EBI-12382151;
CC P55212; A0A0A0MR05: MLST8; NbExp=3; IntAct=EBI-718729, EBI-25835557;
CC P55212; P34949-2: MPI; NbExp=3; IntAct=EBI-718729, EBI-21823432;
CC P55212; Q9BV20: MRI1; NbExp=3; IntAct=EBI-718729, EBI-747381;
CC P55212; Q6IN84-2: MRM1; NbExp=3; IntAct=EBI-718729, EBI-25835707;
CC P55212; A2RUH7: MYBPHL; NbExp=3; IntAct=EBI-718729, EBI-9088235;
CC P55212; P01106: MYC; NbExp=3; IntAct=EBI-718729, EBI-447544;
CC P55212; Q9H7X0: NAA60; NbExp=3; IntAct=EBI-718729, EBI-12260336;
CC P55212; Q15742-2: NAB2; NbExp=3; IntAct=EBI-718729, EBI-25834665;
CC P55212; Q9UJ70-2: NAGK; NbExp=3; IntAct=EBI-718729, EBI-11526455;
CC P55212; Q8NDH3-5: NPEPL1; NbExp=3; IntAct=EBI-718729, EBI-12329915;
CC P55212; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-718729, EBI-741158;
CC P55212; P36639-4: NUDT1; NbExp=3; IntAct=EBI-718729, EBI-25834643;
CC P55212; Q8NFH4: NUP37; NbExp=3; IntAct=EBI-718729, EBI-2563158;
CC P55212; Q8NFH3: NUP43; NbExp=3; IntAct=EBI-718729, EBI-1059321;
CC P55212; Q7Z3B4: NUP54; NbExp=3; IntAct=EBI-718729, EBI-741048;
CC P55212; Q3SX64: ODF3L2; NbExp=3; IntAct=EBI-718729, EBI-6660184;
CC P55212; Q6N063-2: OGFOD2; NbExp=3; IntAct=EBI-718729, EBI-22006224;
CC P55212; Q6GQQ9-2: OTUD7B; NbExp=3; IntAct=EBI-718729, EBI-25830200;
CC P55212; Q9H8K7: PAAT; NbExp=3; IntAct=EBI-718729, EBI-714785;
CC P55212; Q99447: PCYT2; NbExp=3; IntAct=EBI-718729, EBI-750317;
CC P55212; P27815-4: PDE4A; NbExp=3; IntAct=EBI-718729, EBI-12080840;
CC P55212; O15534: PER1; NbExp=3; IntAct=EBI-718729, EBI-2557276;
CC P55212; Q9BUL5: PHF23; NbExp=3; IntAct=EBI-718729, EBI-722852;
CC P55212; Q00169: PITPNA; NbExp=3; IntAct=EBI-718729, EBI-1042490;
CC P55212; P48739: PITPNB; NbExp=3; IntAct=EBI-718729, EBI-1047143;
CC P55212; P61925: PKIA; NbExp=3; IntAct=EBI-718729, EBI-2682139;
CC P55212; Q58EX7-2: PLEKHG4; NbExp=3; IntAct=EBI-718729, EBI-21503705;
CC P55212; O60664: PLIN3; NbExp=3; IntAct=EBI-718729, EBI-725795;
CC P55212; Q14181: POLA2; NbExp=3; IntAct=EBI-718729, EBI-712752;
CC P55212; P0DPB6: POLR1D; NbExp=3; IntAct=EBI-718729, EBI-359498;
CC P55212; P36954: POLR2I; NbExp=3; IntAct=EBI-718729, EBI-395202;
CC P55212; Q07869: PPARA; NbExp=3; IntAct=EBI-718729, EBI-78615;
CC P55212; O60927: PPP1R11; NbExp=3; IntAct=EBI-718729, EBI-1048104;
CC P55212; Q6ZMI0-5: PPP1R21; NbExp=3; IntAct=EBI-718729, EBI-25835994;
CC P55212; P54619: PRKAG1; NbExp=3; IntAct=EBI-718729, EBI-1181439;
CC P55212; Q8NCQ7-2: PROCA1; NbExp=3; IntAct=EBI-718729, EBI-25836043;
CC P55212; P41222: PTGDS; NbExp=3; IntAct=EBI-718729, EBI-948821;
CC P55212; P29074: PTPN4; NbExp=3; IntAct=EBI-718729, EBI-710431;
CC P55212; Q8WUD1-2: RAB2B; NbExp=3; IntAct=EBI-718729, EBI-25835884;
CC P55212; Q5R372-9: RABGAP1L; NbExp=3; IntAct=EBI-718729, EBI-10699389;
CC P55212; Q9HD47-3: RANGRF; NbExp=3; IntAct=EBI-718729, EBI-9089733;
CC P55212; Q09028: RBBP4; NbExp=3; IntAct=EBI-718729, EBI-620823;
CC P55212; Q04206: RELA; NbExp=3; IntAct=EBI-718729, EBI-73886;
CC P55212; P47804-3: RGR; NbExp=3; IntAct=EBI-718729, EBI-25834767;
CC P55212; Q15382: RHEB; NbExp=3; IntAct=EBI-718729, EBI-1055287;
CC P55212; Q06587: RING1; NbExp=3; IntAct=EBI-718729, EBI-752313;
CC P55212; Q8N5U6: RNF10; NbExp=3; IntAct=EBI-718729, EBI-714023;
CC P55212; P62701: RPS4X; NbExp=3; IntAct=EBI-718729, EBI-354303;
CC P55212; Q66K80: RUSC1-AS1; NbExp=3; IntAct=EBI-718729, EBI-10248967;
CC P55212; Q01826: SATB1; NbExp=2; IntAct=EBI-718729, EBI-743747;
CC P55212; O15126: SCAMP1; NbExp=3; IntAct=EBI-718729, EBI-954338;
CC P55212; P22307-3: SCP2; NbExp=3; IntAct=EBI-718729, EBI-25834804;
CC P55212; Q9BRK5: SDF4; NbExp=3; IntAct=EBI-718729, EBI-1389808;
CC P55212; Q9NTN9-3: SEMA4G; NbExp=3; IntAct=EBI-718729, EBI-9089805;
CC P55212; P01011: SERPINA3; NbExp=3; IntAct=EBI-718729, EBI-296557;
CC P55212; Q15393: SF3B3; NbExp=3; IntAct=EBI-718729, EBI-346977;
CC P55212; Q9NR46: SH3GLB2; NbExp=3; IntAct=EBI-718729, EBI-749607;
CC P55212; Q9BZQ2: SHCBP1L; NbExp=3; IntAct=EBI-718729, EBI-10818532;
CC P55212; O60902-3: SHOX2; NbExp=3; IntAct=EBI-718729, EBI-9092164;
CC P55212; Q86US8: SMG6; NbExp=3; IntAct=EBI-718729, EBI-3232100;
CC P55212; P37840: SNCA; NbExp=3; IntAct=EBI-718729, EBI-985879;
CC P55212; Q96H20: SNF8; NbExp=3; IntAct=EBI-718729, EBI-747719;
CC P55212; Q13573: SNW1; NbExp=3; IntAct=EBI-718729, EBI-632715;
CC P55212; Q7Z6I5: SPATA12; NbExp=3; IntAct=EBI-718729, EBI-10696971;
CC P55212; Q496A3: SPATS1; NbExp=3; IntAct=EBI-718729, EBI-3923692;
CC P55212; Q9C004: SPRY4; NbExp=3; IntAct=EBI-718729, EBI-354861;
CC P55212; Q5W111-2: SPRYD7; NbExp=3; IntAct=EBI-718729, EBI-12408727;
CC P55212; Q96BD6: SPSB1; NbExp=3; IntAct=EBI-718729, EBI-2659201;
CC P55212; Q92797-2: SYMPK; NbExp=3; IntAct=EBI-718729, EBI-21560407;
CC P55212; O60506-4: SYNCRIP; NbExp=3; IntAct=EBI-718729, EBI-11123832;
CC P55212; O15273: TCAP; NbExp=3; IntAct=EBI-718729, EBI-954089;
CC P55212; Q86WV5: TEN1; NbExp=3; IntAct=EBI-718729, EBI-2562799;
CC P55212; Q96A09: TENT5B; NbExp=3; IntAct=EBI-718729, EBI-752030;
CC P55212; P54274-2: TERF1; NbExp=3; IntAct=EBI-718729, EBI-711018;
CC P55212; P22735: TGM1; NbExp=3; IntAct=EBI-718729, EBI-2562368;
CC P55212; O43548: TGM5; NbExp=3; IntAct=EBI-718729, EBI-12027348;
CC P55212; Q9NQ88: TIGAR; NbExp=3; IntAct=EBI-718729, EBI-3920747;
CC P55212; Q9UIK5-2: TMEFF2; NbExp=3; IntAct=EBI-718729, EBI-25835153;
CC P55212; Q53NU3: tmp_locus_54; NbExp=3; IntAct=EBI-718729, EBI-10242677;
CC P55212; P04637: TP53; NbExp=3; IntAct=EBI-718729, EBI-366083;
CC P55212; Q12888: TP53BP1; NbExp=3; IntAct=EBI-718729, EBI-396540;
CC P55212; P36406: TRIM23; NbExp=3; IntAct=EBI-718729, EBI-740098;
CC P55212; Q86WT6-2: TRIM69; NbExp=3; IntAct=EBI-718729, EBI-11525489;
CC P55212; Q13885: TUBB2A; NbExp=3; IntAct=EBI-718729, EBI-711595;
CC P55212; P49459: UBE2A; NbExp=3; IntAct=EBI-718729, EBI-2339348;
CC P55212; Q9P1Q0-4: VPS54; NbExp=3; IntAct=EBI-718729, EBI-25835297;
CC P55212; Q9NX94: WBP1L; NbExp=3; IntAct=EBI-718729, EBI-10316321;
CC P55212; Q8NA23-2: WDR31; NbExp=3; IntAct=EBI-718729, EBI-25835937;
CC P55212; Q9BQA1: WDR77; NbExp=3; IntAct=EBI-718729, EBI-1237307;
CC P55212; O00755: WNT7A; NbExp=3; IntAct=EBI-718729, EBI-727198;
CC P55212; O95070: YIF1A; NbExp=3; IntAct=EBI-718729, EBI-2799703;
CC P55212; O43829: ZBTB14; NbExp=3; IntAct=EBI-718729, EBI-10176632;
CC P55212; Q8IWT0-2: ZBTB8OS; NbExp=3; IntAct=EBI-718729, EBI-12956041;
CC P55212; Q53FD0-2: ZC2HC1C; NbExp=3; IntAct=EBI-718729, EBI-14104088;
CC P55212; Q05CR2: ZNF248; NbExp=3; IntAct=EBI-718729, EBI-25835471;
CC P55212; Q96JL9-2: ZNF333; NbExp=3; IntAct=EBI-718729, EBI-25835852;
CC P55212; Q96LX8: ZNF597; NbExp=3; IntAct=EBI-718729, EBI-9091553;
CC P55212; Q3KNS6-3: ZNF829; NbExp=3; IntAct=EBI-718729, EBI-18036029;
CC P55212; A0A384MDV8; NbExp=3; IntAct=EBI-718729, EBI-25834468;
CC P55212; B7Z3E8; NbExp=3; IntAct=EBI-718729, EBI-25831617;
CC P55212; Q86V28; NbExp=3; IntAct=EBI-718729, EBI-10259496;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27911442}. Nucleus
CC {ECO:0000269|PubMed:27911442}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Alpha;
CC IsoId=P55212-1; Sequence=Displayed;
CC Name=Beta;
CC IsoId=P55212-2; Sequence=VSP_000805;
CC -!- DOMAIN: The N-terminal disordered prodomain is required to prevent
CC self-activation. {ECO:0000269|PubMed:19133298}.
CC -!- DOMAIN: The Tri-arginine exosite is required to recruit substrates for
CC hydrolysis. {ECO:0000269|PubMed:30420425}.
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 (PubMed:28154009). Other
CC caspases rest constitutively in the strand conformation before and
CC after substrate-binding (PubMed:28154009).
CC {ECO:0000269|PubMed:28154009}.
CC -!- PTM: Phosphorylated by NUAK1; phosphorylation inhibits self-activation
CC (PubMed:15273717, PubMed:22483120). Phosphorylation at Ser-257 by AMP-
CC activated protein kinase (PRKAA1 or PRKAA2) inhibits autocleavage,
CC preventing caspase activation, thereby preventing hepatocyte apoptosis
CC (PubMed:32029622). {ECO:0000269|PubMed:15273717,
CC ECO:0000269|PubMed:22483120, ECO:0000269|PubMed:32029622}.
CC -!- PTM: Palmitoylation by ZDHHC17 blocks dimerization and subsequent
CC activation, leading to inhibit the cysteine protease activity.
CC {ECO:0000269|PubMed:27911442}.
CC -!- PTM: Can be cleaved and activated by different caspases, depending on
CC the context (PubMed:19133298, PubMed:28864531). Cleaved and activated
CC by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3)
CC (PubMed:9463409). 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 (PubMed:19133298, PubMed:28864531).
CC Cleaved and activated by CASP1, possibly in the context of inflammation
CC (PubMed:16123779). {ECO:0000269|PubMed:16123779,
CC ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:28864531,
CC ECO:0000269|PubMed:9463409}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/casp6/";
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DR EMBL; U20536; AAC50168.1; -; mRNA.
DR EMBL; U20537; AAC50169.1; -; mRNA.
DR EMBL; AY254046; AAO63494.1; -; Genomic_DNA.
DR EMBL; BC000305; AAH00305.1; -; mRNA.
DR EMBL; BC004460; AAH04460.1; -; mRNA.
DR CCDS; CCDS3684.1; -. [P55212-1]
DR CCDS; CCDS3685.1; -. [P55212-2]
DR RefSeq; NP_001217.2; NM_001226.3. [P55212-1]
DR RefSeq; NP_116787.1; NM_032992.2. [P55212-2]
DR PDB; 2WDP; X-ray; 1.95 A; A/B/C/D=1-293.
DR PDB; 3K7E; X-ray; 3.00 A; A/B/C/D=24-293.
DR PDB; 3NKF; X-ray; 2.90 A; A/B/C/D=24-293.
DR PDB; 3NR2; X-ray; 2.90 A; A/B=24-293.
DR PDB; 3OD5; X-ray; 1.60 A; A/B=24-293.
DR PDB; 3P45; X-ray; 2.53 A; A/C/E/G/I/K/M/O=1-179, B/D/F/H/J/L/N/P=193-293.
DR PDB; 3P4U; X-ray; 1.90 A; A/C=23-179, B/D=193-293.
DR PDB; 3QNW; X-ray; 2.65 A; A/C/E/G=24-179, B/D/F/H=194-293.
DR PDB; 3S70; X-ray; 1.62 A; A/C=24-293.
DR PDB; 3S8E; X-ray; 2.88 A; A/B/C/D/E/F/G/H=24-293.
DR PDB; 3V6L; X-ray; 2.20 A; A/B=21-293.
DR PDB; 3V6M; X-ray; 2.69 A; A/B/C/D/F/G/I/J=24-293.
DR PDB; 4EJF; X-ray; 2.65 A; A/B/C/D=24-293.
DR PDB; 4FXO; X-ray; 2.85 A; A/B/C/D=1-293.
DR PDB; 4HVA; X-ray; 2.07 A; A/B=24-293.
DR PDB; 4IYR; X-ray; 2.70 A; A/B=1-293.
DR PDB; 4N5D; X-ray; 2.06 A; A/B=24-293.
DR PDB; 4N6G; X-ray; 2.14 A; A/B=24-293.
DR PDB; 4N7J; X-ray; 1.67 A; A/B=24-293.
DR PDB; 4N7M; X-ray; 2.12 A; A/B=24-293.
DR PDB; 4NBK; X-ray; 1.94 A; A/B=24-293.
DR PDB; 4NBL; X-ray; 1.76 A; A/B=24-293.
DR PDB; 4NBN; X-ray; 1.75 A; A/B=24-293.
DR PDB; 6DEU; X-ray; 2.80 A; A/B=2-293.
DR PDB; 6DEV; X-ray; 2.35 A; A/B/C/D=2-293.
DR PDBsum; 2WDP; -.
DR PDBsum; 3K7E; -.
DR PDBsum; 3NKF; -.
DR PDBsum; 3NR2; -.
DR PDBsum; 3OD5; -.
DR PDBsum; 3P45; -.
DR PDBsum; 3P4U; -.
DR PDBsum; 3QNW; -.
DR PDBsum; 3S70; -.
DR PDBsum; 3S8E; -.
DR PDBsum; 3V6L; -.
DR PDBsum; 3V6M; -.
DR PDBsum; 4EJF; -.
DR PDBsum; 4FXO; -.
DR PDBsum; 4HVA; -.
DR PDBsum; 4IYR; -.
DR PDBsum; 4N5D; -.
DR PDBsum; 4N6G; -.
DR PDBsum; 4N7J; -.
DR PDBsum; 4N7M; -.
DR PDBsum; 4NBK; -.
DR PDBsum; 4NBL; -.
DR PDBsum; 4NBN; -.
DR PDBsum; 6DEU; -.
DR PDBsum; 6DEV; -.
DR AlphaFoldDB; P55212; -.
DR SMR; P55212; -.
DR BioGRID; 107289; 36.
DR ComplexPortal; CPX-971; Caspase-6 complex.
DR DIP; DIP-44649N; -.
DR ELM; P55212; -.
DR IntAct; P55212; 213.
DR MINT; P55212; -.
DR STRING; 9606.ENSP00000265164; -.
DR BindingDB; P55212; -.
DR ChEMBL; CHEMBL3308; -.
DR GuidetoPHARMACOLOGY; 1622; -.
DR MEROPS; C14.005; -.
DR GlyGen; P55212; 1 site, 2 O-linked glycans (1 site).
DR iPTMnet; P55212; -.
DR PhosphoSitePlus; P55212; -.
DR SwissPalm; P55212; -.
DR BioMuta; CASP6; -.
DR DMDM; 26006981; -.
DR OGP; P55212; -.
DR EPD; P55212; -.
DR jPOST; P55212; -.
DR MassIVE; P55212; -.
DR MaxQB; P55212; -.
DR PaxDb; P55212; -.
DR PeptideAtlas; P55212; -.
DR PRIDE; P55212; -.
DR ProteomicsDB; 56817; -. [P55212-1]
DR ProteomicsDB; 56818; -. [P55212-2]
DR Antibodypedia; 1733; 1154 antibodies from 43 providers.
DR DNASU; 839; -.
DR Ensembl; ENST00000265164.7; ENSP00000265164.2; ENSG00000138794.10. [P55212-1]
DR Ensembl; ENST00000352981.7; ENSP00000285333.3; ENSG00000138794.10. [P55212-2]
DR GeneID; 839; -.
DR KEGG; hsa:839; -.
DR MANE-Select; ENST00000265164.7; ENSP00000265164.2; NM_001226.4; NP_001217.2.
DR UCSC; uc003hzn.2; human. [P55212-1]
DR CTD; 839; -.
DR DisGeNET; 839; -.
DR GeneCards; CASP6; -.
DR HGNC; HGNC:1507; CASP6.
DR HPA; ENSG00000138794; Tissue enhanced (intestine).
DR MIM; 601532; gene.
DR neXtProt; NX_P55212; -.
DR OpenTargets; ENSG00000138794; -.
DR PharmGKB; PA26090; -.
DR VEuPathDB; HostDB:ENSG00000138794; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00940000155140; -.
DR HOGENOM; CLU_036904_2_2_1; -.
DR InParanoid; P55212; -.
DR OMA; PAEEYRM; -.
DR OrthoDB; 984395at2759; -.
DR PhylomeDB; P55212; -.
DR TreeFam; TF102023; -.
DR BRENDA; 3.4.22.59; 2681.
DR PathwayCommons; P55212; -.
DR Reactome; R-HSA-111465; Apoptotic cleavage of cellular proteins.
DR Reactome; R-HSA-264870; Caspase-mediated cleavage of cytoskeletal proteins.
DR Reactome; R-HSA-352238; Breakdown of the nuclear lamina.
DR Reactome; R-HSA-6803207; TP53 Regulates Transcription of Caspase Activators and Caspases.
DR SABIO-RK; P55212; -.
DR SignaLink; P55212; -.
DR SIGNOR; P55212; -.
DR BioGRID-ORCS; 839; 11 hits in 1086 CRISPR screens.
DR ChiTaRS; CASP6; human.
DR EvolutionaryTrace; P55212; -.
DR GeneWiki; Caspase_6; -.
DR GenomeRNAi; 839; -.
DR Pharos; P55212; Tchem.
DR PRO; PR:P55212; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P55212; protein.
DR Bgee; ENSG00000138794; Expressed in rectum and 168 other tissues.
DR ExpressionAtlas; P55212; baseline and differential.
DR Genevisible; P55212; HS.
DR GO; GO:0008303; C:caspase complex; IPI:ComplexPortal.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR GO; GO:0005730; C:nucleolus; IDA:ComplexPortal.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; IMP:CAFA.
DR GO; GO:0008234; F:cysteine-type peptidase activity; TAS:ProtInc.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; IDA:ComplexPortal.
DR GO; GO:0002218; P:activation of innate immune response; IDA:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IBA:GO_Central.
DR GO; GO:0072734; P:cellular response to staurosporine; IMP:CAFA.
DR GO; GO:0030855; P:epithelial cell differentiation; IEP:UniProtKB.
DR GO; GO:0097284; P:hepatocyte apoptotic process; IDA:UniProtKB.
DR GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:ComplexPortal.
DR GO; GO:0060545; P:positive regulation of necroptotic process; IDA:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB.
DR GO; GO:1901028; P:regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IC:ComplexPortal.
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 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Autocatalytic cleavage;
KW Cytoplasm; Hydrolase; Lipoprotein; Nucleus; Palmitate; Phosphoprotein;
KW Protease; Reference proteome; Thiol protease; Zymogen.
FT PROPEP 1..23
FT /evidence="ECO:0000305|PubMed:19133298,
FT ECO:0000305|PubMed:8900201, ECO:0000305|PubMed:9463409"
FT /id="PRO_0000004608"
FT CHAIN 24..179
FT /note="Caspase-6 subunit p18"
FT /evidence="ECO:0000305|PubMed:19133298,
FT ECO:0000305|PubMed:8900201, ECO:0000305|PubMed:9463409"
FT /id="PRO_0000004609"
FT PROPEP 180..193
FT /evidence="ECO:0000305|PubMed:19133298,
FT ECO:0000305|PubMed:8900201, ECO:0000305|PubMed:9463409"
FT /id="PRO_0000004610"
FT CHAIN 194..293
FT /note="Caspase-6 subunit p11"
FT /evidence="ECO:0000305|PubMed:19133298,
FT ECO:0000305|PubMed:8900201, ECO:0000305|PubMed:9463409"
FT /id="PRO_0000004611"
FT REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000269|PubMed:28864531,
FT ECO:0000305|PubMed:30420425"
FT REGION 42..44
FT /note="Tri-arginine exosite"
FT /evidence="ECO:0000269|PubMed:30420425"
FT REGION 125..142
FT /note="130's region"
FT /evidence="ECO:0000269|PubMed:28154009"
FT ACT_SITE 121
FT /evidence="ECO:0000269|PubMed:30420425"
FT ACT_SITE 163
FT /evidence="ECO:0000269|PubMed:16123779,
FT ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:19694615,
FT ECO:0000269|PubMed:20890311, ECO:0000269|PubMed:28864531,
FT ECO:0000269|PubMed:30420425"
FT MOD_RES 79
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O08738"
FT MOD_RES 257
FT /note="Phosphoserine; by NUAK1 and AMPK"
FT /evidence="ECO:0000269|PubMed:15273717,
FT ECO:0000269|PubMed:22483120, ECO:0000269|PubMed:32029622"
FT LIPID 264
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:27911442"
FT LIPID 277
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:27911442"
FT VAR_SEQ 14..102
FT /note="Missing (in isoform Beta)"
FT /evidence="ECO:0000303|PubMed:7796396"
FT /id="VSP_000805"
FT VARIANT 35
FT /note="E -> K (in dbSNP:rs11574697)"
FT /id="VAR_029242"
FT VARIANT 109
FT /note="A -> T (in dbSNP:rs5030674)"
FT /id="VAR_016130"
FT VARIANT 182
FT /note="T -> S (in dbSNP:rs5030593)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_020126"
FT MUTAGEN 23
FT /note="D->A: Abolished activation due to the presence of
FT the N-terminal disordered prodomain. Abolished processing
FT and subsequent activation; when associated with A-179 and
FT A-193."
FT /evidence="ECO:0000269|PubMed:19133298,
FT ECO:0000269|PubMed:28864531"
FT MUTAGEN 42..44
FT /note="RRR->AAA: Decreased ability to hydrolyze
FT substrates."
FT /evidence="ECO:0000269|PubMed:30420425"
FT MUTAGEN 121
FT /note="H->A: Catalytically inactive active-site mutant."
FT /evidence="ECO:0000269|PubMed:30420425"
FT MUTAGEN 135
FT /note="E->Q: Increased stability."
FT /evidence="ECO:0000269|PubMed:28154009"
FT MUTAGEN 163
FT /note="C->A,S: Catalytically inactive active-site mutant."
FT /evidence="ECO:0000269|PubMed:16123779,
FT ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:19694615,
FT ECO:0000269|PubMed:20890311, ECO:0000269|PubMed:28864531,
FT ECO:0000269|PubMed:30420425"
FT MUTAGEN 179
FT /note="D->A: Abolished processing and subsequent
FT activation; when associated with A-23 and A-193."
FT /evidence="ECO:0000269|PubMed:19133298,
FT ECO:0000269|PubMed:28864531"
FT MUTAGEN 193
FT /note="D->A: Abolished processing and subsequent
FT activation; when associated with A-23 and A-179."
FT /evidence="ECO:0000269|PubMed:19133298,
FT ECO:0000269|PubMed:28864531"
FT MUTAGEN 257
FT /note="S->A: Abolished phosphorylation, leading to caspase-
FT 6 activation."
FT /evidence="ECO:0000269|PubMed:15273717,
FT ECO:0000269|PubMed:32029622"
FT MUTAGEN 257
FT /note="S->D: Phospho-mimetic mutant; prevents caspase-6
FT autoactivation."
FT /evidence="ECO:0000269|PubMed:22483120,
FT ECO:0000269|PubMed:32029622"
FT MUTAGEN 257
FT /note="S->E: Phospho-mimetic mutant; loss of self-
FT activation."
FT /evidence="ECO:0000269|PubMed:22433863,
FT ECO:0000269|PubMed:32029622"
FT MUTAGEN 264
FT /note="C->S: Reduced palmitoylation, leading to increased
FT cysteine protease activity."
FT /evidence="ECO:0000269|PubMed:27911442"
FT MUTAGEN 277
FT /note="C->S: Reduced palmitoylation, leading to increased
FT cysteine protease activity."
FT /evidence="ECO:0000269|PubMed:27911442"
FT CONFLICT 66
FT /note="G -> R (in Ref. 1; AAC50168)"
FT /evidence="ECO:0000305"
FT STRAND 41..43
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 46..51
FT /evidence="ECO:0007829|PDB:3OD5"
FT HELIX 57..59
FT /evidence="ECO:0007829|PDB:3OD5"
FT HELIX 67..80
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 84..90
FT /evidence="ECO:0007829|PDB:3OD5"
FT HELIX 93..105
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 114..120
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 122..124
FT /evidence="ECO:0007829|PDB:4N7J"
FT STRAND 126..128
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 130..135
FT /evidence="ECO:0007829|PDB:3OD5"
FT HELIX 136..141
FT /evidence="ECO:0007829|PDB:3OD5"
FT TURN 145..147
FT /evidence="ECO:0007829|PDB:3OD5"
FT HELIX 149..151
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 156..162
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 165..167
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 190..194
FT /evidence="ECO:0007829|PDB:4N7J"
FT STRAND 197..199
FT /evidence="ECO:0007829|PDB:3S8E"
FT TURN 202..205
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 206..212
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 219..221
FT /evidence="ECO:0007829|PDB:3OD5"
FT TURN 222..224
FT /evidence="ECO:0007829|PDB:3OD5"
FT HELIX 227..239
FT /evidence="ECO:0007829|PDB:3OD5"
FT TURN 240..242
FT /evidence="ECO:0007829|PDB:3OD5"
FT HELIX 245..258
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 263..265
FT /evidence="ECO:0007829|PDB:4N7J"
FT HELIX 267..269
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 271..273
FT /evidence="ECO:0007829|PDB:3S8E"
FT STRAND 277..280
FT /evidence="ECO:0007829|PDB:3OD5"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:3QNW"
SQ SEQUENCE 293 AA; 33310 MW; 0738AE4F9791EBD7 CRC64;
MSSASGLRRG HPAGGEENMT ETDAFYKREM FDPAEKYKMD HRRRGIALIF NHERFFWHLT
LPERRGTCAD RDNLTRRFSD LGFEVKCFND LKAEELLLKI HEVSTVSHAD ADCFVCVFLS
HGEGNHIYAY DAKIEIQTLT GLFKGDKCHS LVGKPKIFII QACRGNQHDV PVIPLDVVDN
QTEKLDTNIT EVDAASVYTL PAGADFLMCY SVAEGYYSHR ETVNGSWYIQ DLCEMLGKYG
SSLEFTELLT LVNRKVSQRR VDFCKDPSAI GKKQVPCFAS MLTKKLHFFP KSN
