ID CED3_CAEEL Reviewed; 503 AA.
AC P42573; P45435; Q9GQQ4; Q9NAQ8;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 14-AUG-2001, sequence version 2.
DT 27-MAR-2024, entry version 184.
DE RecName: Full=Cell death protein 3;
DE EC=3.4.22.60 {ECO:0000269|PubMed:18776901, ECO:0000269|PubMed:19575016, ECO:0000269|PubMed:25383666, ECO:0000269|PubMed:25432023, ECO:0000269|PubMed:27723735, ECO:0000269|PubMed:8654923, ECO:0000269|PubMed:9857046};
DE AltName: Full=Caspase ced-3 {ECO:0000305};
DE Contains:
DE RecName: Full=Cell death protein 3 subunit p17 {ECO:0000305|PubMed:8654923};
DE Contains:
DE RecName: Full=Cell death protein 3 subunit p15 {ECO:0000305|PubMed:8654923};
DE Contains:
DE RecName: Full=Cell death protein 3 subunit p13 {ECO:0000305|PubMed:8654923};
DE Flags: Precursor;
GN Name=ced-3 {ECO:0000312|WormBase:C48D1.2a};
GN ORFNames=C48D1.2 {ECO:0000312|WormBase:C48D1.2a};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND DEVELOPMENTAL STAGE.
RC STRAIN=Bristol N2;
RX PubMed=8242740; DOI=10.1016/0092-8674(93)90485-9;
RA Yuan J., Shaham S., Ledoux S., Ellis H.M., Horvitz H.R.;
RT "The C. elegans cell death gene ced-3 encodes a protein similar to
RT mammalian interleukin-1 beta-converting enzyme.";
RL Cell 75:641-652(1993).
RN [2]
RP SEQUENCE REVISION TO 418.
RA Horvitz H.R.;
RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2;
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [4]
RP PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY
RP REGULATION, PROTEOLYTIC CLEAVAGE, ACTIVE SITE, AND MUTAGENESIS OF CYS-358;
RP GLY-360; ALA-449 AND GLY-474.
RX PubMed=8654923; DOI=10.1101/gad.10.9.1073;
RA Xue D., Shaham S., Horvitz H.R.;
RT "The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease
RT with substrate specificities similar to those of the human CPP32
RT protease.";
RL Genes Dev. 10:1073-1083(1996).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF LEU-27; GLY-65 AND ALA-449.
RX PubMed=3955651; DOI=10.1016/0092-8674(86)90004-8;
RA Ellis H.M., Horvitz H.R.;
RT "Genetic control of programmed cell death in the nematode C. elegans.";
RL Cell 44:817-829(1986).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PROTEOLYTIC CLEAVAGE,
RP ACTIVE SITE, AND MUTAGENESIS OF CYS-358.
RC STRAIN=Bristol N2;
RX PubMed=9857046; DOI=10.1074/jbc.273.52.35109;
RA Shaham S.;
RT "Identification of multiple Caenorhabditis elegans caspases and their
RT potential roles in proteolytic cascades.";
RL J. Biol. Chem. 273:35109-35117(1998).
RN [7]
RP FUNCTION.
RX PubMed=9927601; DOI=10.1242/dev.126.5.1011;
RA Gumienny T.L., Lambie E., Hartwieg E., Horvitz H.R., Hengartner M.O.;
RT "Genetic control of programmed cell death in the Caenorhabditis elegans
RT hermaphrodite germline.";
RL Development 126:1011-1022(1999).
RN [8]
RP IDENTIFICATION IN A CED-3; CED-4 AND MAC-1 COMPLEX.
RX PubMed=10101135; DOI=10.1242/dev.126.9.2021;
RA Wu D., Chen P.J., Chen S., Hu Y., Nunez G., Ellis R.E.;
RT "C. elegans MAC-1, an essential member of the AAA family of ATPases, can
RT bind CED-4 and prevent cell death.";
RL Development 126:2021-2031(1999).
RN [9]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=10764728; DOI=10.1074/jbc.c000146200;
RA Chan S.L., Yee K.S., Tan K.M., Yu V.C.;
RT "The Caenorhabditis elegans sex determination protein FEM-1 is a CED-3
RT substrate that associates with CED-4 and mediates apoptosis in mammalian
RT cells.";
RL J. Biol. Chem. 275:17925-17928(2000).
RN [10]
RP INTERACTION WITH DCT-1.
RX PubMed=11114722; DOI=10.1038/sj.onc.1203929;
RA Cizeau J., Ray R., Chen G., Gietz R.D., Greenberg A.H.;
RT "The C. elegans orthologue ceBNIP3 interacts with CED-9 and CED-3 but kills
RT through a BH3- and caspase-independent mechanism.";
RL Oncogene 19:5453-5463(2000).
RN [11]
RP FUNCTION, AND MUTAGENESIS OF GLY-360.
RX PubMed=11226309; DOI=10.1073/pnas.041613098;
RA Aballay A., Ausubel F.M.;
RT "Programmed cell death mediated by ced-3 and ced-4 protects Caenorhabditis
RT elegans from Salmonella typhimurium-mediated killing.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:2735-2739(2001).
RN [12]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=17329362; DOI=10.1242/dev.02818;
RA Maurer C.W., Chiorazzi M., Shaham S.;
RT "Timing of the onset of a developmental cell death is controlled by
RT transcriptional induction of the C. elegans ced-3 caspase-encoding gene.";
RL Development 134:1357-1368(2007).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND PROTEOLYTIC
RP CLEAVAGE.
RX PubMed=17371877; DOI=10.1074/jbc.m611051200;
RA Taylor R.C., Brumatti G., Ito S., Hengartner M.O., Derry W.B., Martin S.J.;
RT "Establishing a blueprint for CED-3-dependent killing through
RT identification of multiple substrates for this protease.";
RL J. Biol. Chem. 282:15011-15021(2007).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF GLY-474.
RX PubMed=18722182; DOI=10.1016/j.molcel.2008.07.015;
RA Breckenridge D.G., Kang B.H., Kokel D., Mitani S., Staehelin L.A., Xue D.;
RT "Caenorhabditis elegans drp-1 and fis-2 regulate distinct cell-death
RT execution pathways downstream of ced-3 and independent of ced-9.";
RL Mol. Cell 31:586-597(2008).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH CSP-3,
RP PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF GLY-474.
RX PubMed=18776901; DOI=10.1038/nsmb.1488;
RA Geng X., Shi Y., Nakagawa A., Yoshina S., Mitani S., Shi Y., Xue D.;
RT "Inhibition of CED-3 zymogen activation and apoptosis in Caenorhabditis
RT elegans by caspase homolog CSP-3.";
RL Nat. Struct. Mol. Biol. 15:1094-1101(2008).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH CSP-2,
RP AND PROTEOLYTIC CLEAVAGE.
RX PubMed=19575016; DOI=10.1038/cdd.2009.88;
RA Geng X., Zhou Q.H., Kage-Nakadai E., Shi Y., Yan N., Mitani S., Xue D.;
RT "Caenorhabditis elegans caspase homolog CSP-2 inhibits CED-3 autoactivation
RT and apoptosis in germ cells.";
RL Cell Death Differ. 16:1385-1394(2009).
RN [17]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH CED-4, AND
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=20434985; DOI=10.1016/j.cell.2010.03.017;
RA Qi S., Pang Y., Hu Q., Liu Q., Li H., Zhou Y., He T., Liang Q., Liu Y.,
RA Yuan X., Luo G., Li H., Wang J., Yan N., Shi Y.;
RT "Crystal structure of the Caenorhabditis elegans apoptosome reveals an
RT octameric assembly of CED-4.";
RL Cell 141:446-457(2010).
RN [18]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=20223951; DOI=10.1126/science.1182374;
RA Nakagawa A., Shi Y., Kage-Nakadai E., Mitani S., Xue D.;
RT "Caspase-dependent conversion of Dicer ribonuclease into a death-promoting
RT deoxyribonuclease.";
RL Science 328:327-334(2010).
RN [19]
RP FUNCTION.
RX PubMed=21901106; DOI=10.1371/journal.pgen.1002238;
RA Rutkowski R., Dickinson R., Stewart G., Craig A., Schimpl M., Keyse S.M.,
RA Gartner A.;
RT "Regulation of Caenorhabditis elegans p53/CEP-1-dependent germ cell
RT apoptosis by Ras/MAPK signaling.";
RL PLoS Genet. 7:E1002238-E1002238(2011).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=21909434; DOI=10.1371/journal.pone.0024444;
RA Contreras V., Friday A.J., Morrison J.K., Hao E., Keiper B.D.;
RT "Cap-independent translation promotes C. elegans germ cell apoptosis
RT through Apaf-1/CED-4 in a caspase-dependent mechanism.";
RL PLoS ONE 6:E24444-E24444(2011).
RN [21]
RP FUNCTION, AND MUTAGENESIS OF GLY-360.
RX PubMed=22629231; DOI=10.1371/journal.pbio.1001331;
RA Pinan-Lucarre B., Gabel C.V., Reina C.P., Hulme S.E., Shevkoplyas S.S.,
RA Slone R.D., Xue J., Qiao Y., Weisberg S., Roodhouse K., Sun L.,
RA Whitesides G.M., Samuel A., Driscoll M.;
RT "The core apoptotic executioner proteins CED-3 and CED-4 promote initiation
RT of neuronal regeneration in Caenorhabditis elegans.";
RL PLoS Biol. 10:E1001331-E1001331(2012).
RN [22]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=24225442; DOI=10.1038/ncomms3726;
RA Chen Y.Z., Mapes J., Lee E.S., Skeen-Gaar R.R., Xue D.;
RT "Caspase-mediated activation of Caenorhabditis elegans CED-8 promotes
RT apoptosis and phosphatidylserine externalization.";
RL Nat. Commun. 4:2726-2726(2013).
RN [23]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=25432023; DOI=10.7554/elife.04265;
RA Weaver B.P., Zabinsky R., Weaver Y.M., Lee E.S., Xue D., Han M.;
RT "CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression
RT dynamics for robust development in C. elegans.";
RL Elife 3:E04265-E04265(2014).
RN [24]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=25383666; DOI=10.1038/nsmb.2915;
RA Nakagawa A., Sullivan K.D., Xue D.;
RT "Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by
RT inhibiting the AKT pathway.";
RL Nat. Struct. Mol. Biol. 21:1082-1090(2014).
RN [25]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP GLY-366.
RX PubMed=26074078; DOI=10.1016/j.celrep.2015.05.031;
RA Meng L., Mulcahy B., Cook S.J., Neubauer M., Wan A., Jin Y., Yan D.;
RT "The cell death pathway regulates synapse elimination through cleavage of
RT gelsolin in Caenorhabditis elegans neurons.";
RL Cell Rep. 11:1737-1748(2015).
RN [26]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH NPP-14,
RP SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF LEU-27;
RP LEU-30; ARG-51; GLY-65 AND GLY-360.
RX PubMed=27723735; DOI=10.1038/nsmb.3308;
RA Chen X., Wang Y., Chen Y.Z., Harry B.L., Nakagawa A., Lee E.S., Guo H.,
RA Xue D.;
RT "Regulation of CED-3 caspase localization and activation by C. elegans
RT nuclear-membrane protein NPP-14.";
RL Nat. Struct. Mol. Biol. 23:958-964(2016).
RN [27]
RP FUNCTION, IDENTIFICATION IN COMPLEX WITH ATE-1 AND UBR-1, AND MUTAGENESIS
RP OF CYS-358.
RX PubMed=28602583; DOI=10.1016/j.devcel.2017.05.013;
RA Weaver B.P., Weaver Y.M., Mitani S., Han M.;
RT "Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and
RT Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic
RT Development.";
RL Dev. Cell 41:665-673(2017).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.66 ANGSTROMS) OF 198-503 IN COMPLEX WITH CED-4,
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, DOMAIN, REGION, ACTIVE SITE, AND
RP MUTAGENESIS OF CYS-358 AND 391-LEU--ASN-393.
RX PubMed=24065769; DOI=10.1101/gad.224428.113;
RA Huang W., Jiang T., Choi W., Qi S., Pang Y., Hu Q., Xu Y., Gong X.,
RA Jeffrey P.D., Wang J., Shi Y.;
RT "Mechanistic insights into CED-4-mediated activation of CED-3.";
RL Genes Dev. 27:2039-2048(2013).
CC -!- FUNCTION: Acts as a cysteine protease in controlling programmed cell
CC death (apoptosis) by proteolytically activating or inactivating a wide
CC range of substrates (PubMed:8654923, PubMed:3955651, PubMed:18722182,
CC PubMed:26074078, PubMed:27723735). Component of the egl-1, ced-9, ced-4
CC and ced-3 apoptotic signaling cascade required for the initiation of
CC programmed cell death in cells fated to die during embryonic and
CC postembryonic development (PubMed:3955651, PubMed:17329362,
CC PubMed:25432023, PubMed:27723735). During oogenesis, required for
CC germline apoptosis downstream of ced-9 and ced-4 but independently of
CC egl-1 (PubMed:9927601). By cleaving and activating ced-8, promotes
CC phosphatidylserine exposure on the surface of apoptotic cells;
CC phosphatidylserine is a specific marker only present at the surface of
CC apoptotic cells and acts as a specific signal for engulfment
CC (PubMed:24225442). By cleaving and converting dcr-1 into a
CC deoxyribonuclease (DNase), promotes apoptotic chromosomal DNA
CC fragmentation (PubMed:20223951). By cleaving mitochondrial fission
CC protein drp-1, may regulate the removal of mitochondria during
CC apoptosis (PubMed:18722182). During germline apoptosis, cleaves
CC translation initiation factor ifg-1 (isoform p170) promoting cap-
CC independent translation (PubMed:21909434). During male tail
CC morphogenesis, promotes apoptosis of the tail-spike cell downstream of
CC ced-4 but independently of egl-1 and ced-9 (PubMed:17329362). By
CC cleaving cnt-1, prevents the activation of the prosurvival akt-1/2
CC signaling pathway and thus promotes apoptosis (PubMed:25383666).
CC Downstream of ced-4, may play a role in sex-specific cell apoptosis by
CC cleaving sex-determining protein fem-1 (PubMed:10764728). May regulate
CC germline apoptosis in response to DNA damage, probably downstream of
CC let-60/ras and mpk-1 pathway (PubMed:21901106). Cleaves ced-9 in vitro
CC (PubMed:17371877, PubMed:18776901, PubMed:19575016, PubMed:25432023,
CC PubMed:27723735). Cleaves csp-2 isoform b resulting in the removal of
CC the propeptide and the generation of csp-2 subunit p31 in vitro
CC (PubMed:9857046). Independently of its apoptotic role has additional
CC functions. Probably by cleaving and thereby activating actin-severing
CC protein gsnl-1, required for the elimination of transient presynaptic
CC components during larval development downstream of egl-1, ced-9 and
CC ced-4 pathway (PubMed:26074078). Together with ain-1, a component of
CC the miRNA-induced-silencing complex (miRISC), regulates temporal cell
CC fate patterning during larval development (PubMed:25432023). In complex
CC with ubr-1, which is E3 ubiquitin-protein ligase and component of the
CC N-end rule pathway, acts in seam cell fate patterning during larval
CC development by cleaving the heterochronic protein lin-28, and promoting
CC its degradation (PubMed:25432023, PubMed:28602583). Also cleaves
CC heterochronic protein lin-14 and exonuclease disl-2 in vitro
CC (PubMed:25432023). Downstream of calreticulin crt-1 and ced-4 and
CC independently of egl-1 and ced-9, plays a role in the initial steps of
CC axonal regrowth following axotomy (PubMed:22629231). Cleaves 14-3-3-
CC like protein ftt-2, tubulin tbb-2 and calreticulin crt-1 in vitro
CC (PubMed:17371877). Also plays a role in resistance to S.typhimurium-
CC mediated infection (PubMed:11226309). {ECO:0000269|PubMed:10764728,
CC ECO:0000269|PubMed:11226309, ECO:0000269|PubMed:17329362,
CC ECO:0000269|PubMed:17371877, ECO:0000269|PubMed:18722182,
CC ECO:0000269|PubMed:18776901, ECO:0000269|PubMed:19575016,
CC ECO:0000269|PubMed:20223951, ECO:0000269|PubMed:21901106,
CC ECO:0000269|PubMed:21909434, ECO:0000269|PubMed:22629231,
CC ECO:0000269|PubMed:24225442, ECO:0000269|PubMed:25383666,
CC ECO:0000269|PubMed:25432023, ECO:0000269|PubMed:26074078,
CC ECO:0000269|PubMed:27723735, ECO:0000269|PubMed:28602583,
CC ECO:0000269|PubMed:3955651, ECO:0000269|PubMed:8654923,
CC ECO:0000269|PubMed:9857046, ECO:0000269|PubMed:9927601}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Strict requirement for an Asp residue at position P1 and has a
CC preferred cleavage sequence of Asp-Glu-Val-Asp-|-.; EC=3.4.22.60;
CC Evidence={ECO:0000269|PubMed:10764728, ECO:0000269|PubMed:17371877,
CC ECO:0000269|PubMed:18722182, ECO:0000269|PubMed:18776901,
CC ECO:0000269|PubMed:19575016, ECO:0000269|PubMed:20223951,
CC ECO:0000269|PubMed:21909434, ECO:0000269|PubMed:24065769,
CC ECO:0000269|PubMed:24225442, ECO:0000269|PubMed:25383666,
CC ECO:0000269|PubMed:25432023, ECO:0000269|PubMed:27723735,
CC ECO:0000269|PubMed:8654923, ECO:0000269|PubMed:9857046,
CC ECO:0000305|PubMed:26074078};
CC -!- ACTIVITY REGULATION: Octameric ced-4 activates zymogen autoprocessing
CC and enhances activity of processed ced-3 (PubMed:18776901,
CC PubMed:19575016, PubMed:27723735, PubMed:24065769, PubMed:20434985).
CC Zymogen autoactivation is inhibited by csp-3 (PubMed:18776901). csp-3
CC has no effect on active ced-3 (PubMed:18776901). Zymogen autoactivation
CC is inhibited by csp-2 (PubMed:19575016). Inhibited by cysteine protease
CC inhibitor iodoacetic acid (CH3COOI) (PubMed:8654923, PubMed:9857046,
CC PubMed:18776901, PubMed:19575016, PubMed:27723735). Inhibited by
CC benzyloxycarbonyl-DEVD-fluoro-methyl ketone (zDEVD-fmk)
CC (PubMed:8654923, PubMed:9857046, PubMed:25432023). Inhibited by
CC benzyloxycarbonyl-VAD-fluoro-methyl ketone (zVAD-fmk) (PubMed:17371877,
CC PubMed:21909434). Not inhibited by N-[N-(L-3-transcarboxirane-2-
CC carbonyl)-leucyl]-agmatine (E-64) or by the serine and cysteine
CC protease inhibitor L-1-chloro-3-[4-to-osylamido]-7-amino-2-heptanone
CC (TLCK) (PubMed:8654923, PubMed:9857046). {ECO:0000269|PubMed:17371877,
CC ECO:0000269|PubMed:18776901, ECO:0000269|PubMed:19575016,
CC ECO:0000269|PubMed:20434985, ECO:0000269|PubMed:21909434,
CC ECO:0000269|PubMed:24065769, ECO:0000269|PubMed:25432023,
CC ECO:0000269|PubMed:27723735, ECO:0000269|PubMed:8654923,
CC ECO:0000269|PubMed:9857046}.
CC -!- SUBUNIT: The active form is probably a heterodimer of the p17 subunit
CC with either the p15 or p13 subunit which are all derived from the
CC precursor by autocatalysis (Probable). Interacts with octameric ced-4
CC (two ced-3 zymogens per one ced-4 octamer); the interaction causes the
CC autoproteolytic cleavage and activation of ced-3 (PubMed:20434985,
CC PubMed:24065769). Processed ced-3 also interacts with ced-4 octamer to
CC form a stable holoenzyme (PubMed:20434985). Interacts (via large
CC subunit p17) with csp-3; the interaction prevents ced-3 autoactivation
CC and delays ced-4-induced ced-3 processing (PubMed:18776901). Interacts
CC (via large subunit p17 or small subunit p13 or p15) with csp-2; the
CC interaction inhibits ced-3 autoactivation (PubMed:19575016). Interacts
CC (via propeptide) with nucleoporin npp-14; the interaction tethers ced-3
CC to the nuclear membrane and prevents its autoprocessing in absence of
CC ced-4 (PubMed:27723735). Interacts with dct-1 (PubMed:11114722). May
CC form a complex composed of ced-3, ced-4 and mac-1 (PubMed:10101135).
CC Component of a complex containing at least ced-3, ubr-1 and possibly
CC ate-1 (PubMed:28602583). Within complex interacts (via the p17 subunit)
CC with ubr-1; this interaction is required for the ced-3-mediated
CC cleavage and subsequent degradation of the heterochronic protein lin-28
CC (PubMed:28602583). Interacts with ate-1 (isoform a and isoform d);
CC interaction with ate-1 (isoform a) is in the presence or absent of ubr-
CC 1 (PubMed:28602583). {ECO:0000269|PubMed:10101135,
CC ECO:0000269|PubMed:11114722, ECO:0000269|PubMed:18776901,
CC ECO:0000269|PubMed:19575016, ECO:0000269|PubMed:20434985,
CC ECO:0000269|PubMed:24065769, ECO:0000269|PubMed:27723735,
CC ECO:0000269|PubMed:28602583, ECO:0000305}.
CC -!- INTERACTION:
CC P42573; P42573: ced-3; NbExp=7; IntAct=EBI-494247, EBI-494247;
CC P42573; P30429: ced-4; NbExp=10; IntAct=EBI-494247, EBI-494118;
CC P42573; P30429-2: ced-4; NbExp=13; IntAct=EBI-494247, EBI-536271;
CC P42573; P41958: ced-9; NbExp=4; IntAct=EBI-494247, EBI-494110;
CC P42573; G5ECW5: csp-3; NbExp=3; IntAct=EBI-494247, EBI-15727537;
CC -!- SUBCELLULAR LOCATION: Nucleus membrane {ECO:0000269|PubMed:27723735}.
CC Perikaryon {ECO:0000269|PubMed:26074078}. Synapse
CC {ECO:0000269|PubMed:26074078}. Mitochondrion
CC {ECO:0000269|PubMed:26074078}. Cytoplasm {ECO:0000269|PubMed:27723735}.
CC Cytoplasm, perinuclear region {ECO:0000269|PubMed:27723735}.
CC Note=Colocalizes with nucleoporin npp-14 to the perinuclear region in
CC germ cells (PubMed:27723735). Becomes diffused in the cytoplasm in
CC apoptotic germ cells (PubMed:27723735). Localizes to axonal
CC mitochondria and synapses of DD motor neurons (PubMed:26074078).
CC Synaptic localization is dependent on axonal mitochondria
CC (PubMed:26074078). {ECO:0000269|PubMed:26074078,
CC ECO:0000269|PubMed:27723735}.
CC -!- DEVELOPMENTAL STAGE: Highly expressed in embryos and to a lesser extent
CC in adults (PubMed:8242740). Expression is low throughout the larval
CC stage (PubMed:8242740). Expressed in all cells, except intestinal cells
CC and their precursors, starting at around 100-150 minutes post-
CC fertilization and continuing throughout the comma stage of
CC embryogenesis (PubMed:17329362). Not expressed after the 3-fold
CC embryonic stage, and only expressed in 2-3 cells in larvae and adults
CC (PubMed:17329362). In males, expressed in the tail at the L4 larval
CC stage (PubMed:17329362). Expression in the tail-spike cell is
CC restricted to the 3-fold embryonic stage prior to the tail-spike cell
CC death (PubMed:17329362). {ECO:0000269|PubMed:17329362,
CC ECO:0000269|PubMed:8242740}.
CC -!- DOMAIN: The CARD domain is involved in ced-4 binding.
CC {ECO:0000269|PubMed:24065769}.
CC -!- PTM: Autocatalytic cleavage removes the propeptide and generates the
CC catalytic subunit p17 and two non-catalytic subunits p15 and p13;
CC autoproteolysis is induced by ced-4 oligomer (PubMed:8654923,
CC PubMed:9857046, PubMed:17371877, PubMed:18776901, PubMed:19575016,
CC PubMed:27723735, PubMed:20434985). Cleaved by caspase csp-1 probably at
CC Asp-144 and Asp-374 (PubMed:9857046). {ECO:0000269|PubMed:18776901,
CC ECO:0000269|PubMed:19575016, ECO:0000269|PubMed:20434985,
CC ECO:0000269|PubMed:27723735, ECO:0000269|PubMed:8654923,
CC ECO:0000269|PubMed:9857046}.
CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown causes a rupture of the
CC vulva and an increase in laid oocytes in a small proportion of animals.
CC In an ain-1 mutant background, enhances the proportion of animals
CC arrested at the larval stage, with egg-laying defects and with a
CC ruptured vulva. {ECO:0000269|PubMed:25432023}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
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DR EMBL; L29052; AAA27982.2; -; Genomic_DNA.
DR EMBL; AF210702; AAG42045.1; -; mRNA.
DR EMBL; BX284604; CAB61001.2; -; Genomic_DNA.
DR PIR; A49429; A49429.
DR RefSeq; NP_001255708.1; NM_001268779.1.
DR PDB; 4M9R; X-ray; 2.66 A; A/B=198-503.
DR PDB; 4M9S; X-ray; 3.21 A; E/F/G/H=390-397.
DR PDB; 4M9X; X-ray; 3.34 A; C/D=390-395.
DR PDB; 4M9Y; X-ray; 4.20 A; C/D=390-397.
DR PDB; 4M9Z; X-ray; 3.40 A; E/F/G/H=390-397.
DR PDB; 8JOL; EM; 3.00 A; C=1-503.
DR PDBsum; 4M9R; -.
DR PDBsum; 4M9S; -.
DR PDBsum; 4M9X; -.
DR PDBsum; 4M9Y; -.
DR PDBsum; 4M9Z; -.
DR PDBsum; 8JOL; -.
DR AlphaFoldDB; P42573; -.
DR EMDB; EMD-36459; -.
DR SMR; P42573; -.
DR BioGRID; 43363; 91.
DR ComplexPortal; CPX-1358; ced-3-ced-4-mac-1 complex.
DR ComplexPortal; CPX-1360; ced-3-ced-4 caspase complex.
DR DIP; DIP-244N; -.
DR IntAct; P42573; 6.
DR MINT; P42573; -.
DR STRING; 6239.C48D1.2a.1; -.
DR ChEMBL; CHEMBL1250361; -.
DR MEROPS; C14.002; -.
DR EPD; P42573; -.
DR PaxDb; 6239-C48D1-2a; -.
DR PeptideAtlas; P42573; -.
DR EnsemblMetazoa; C48D1.2a.1; C48D1.2a.1; WBGene00000417.
DR GeneID; 178272; -.
DR KEGG; cel:CELE_C48D1.2; -.
DR UCSC; C48D1.2; c. elegans.
DR AGR; WB:WBGene00000417; -.
DR WormBase; C48D1.2a; CE29088; WBGene00000417; ced-3.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00970000196149; -.
DR HOGENOM; CLU_036904_5_2_1; -.
DR InParanoid; P42573; -.
DR OMA; VQSICEV; -.
DR OrthoDB; 2873736at2759; -.
DR PhylomeDB; P42573; -.
DR Reactome; R-CEL-111465; Apoptotic cleavage of cellular proteins.
DR Reactome; R-CEL-140342; Apoptosis induced DNA fragmentation.
DR Reactome; R-CEL-2028269; Signaling by Hippo.
DR Reactome; R-CEL-264870; Caspase-mediated cleavage of cytoskeletal proteins.
DR Reactome; R-CEL-351906; Apoptotic cleavage of cell adhesion proteins.
DR Reactome; R-CEL-418889; Caspase activation via Dependence Receptors in the absence of ligand.
DR Reactome; R-CEL-5357905; Regulation of TNFR1 signaling.
DR PRO; PR:P42573; -.
DR Proteomes; UP000001940; Chromosome IV.
DR Bgee; WBGene00000417; Expressed in adult organism and 7 other cell types or tissues.
DR ExpressionAtlas; P42573; baseline and differential.
DR GO; GO:0008303; C:caspase complex; IDA:ComplexPortal.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IDA:WormBase.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IDA:UniProtKB.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:WormBase.
DR GO; GO:0098793; C:presynapse; IDA:UniProtKB.
DR GO; GO:0008656; F:cysteine-type endopeptidase activator activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:WormBase.
DR GO; GO:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; IDA:WormBase.
DR GO; GO:0004175; F:endopeptidase activity; IDA:WormBase.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0030042; P:actin filament depolymerization; IMP:UniProtKB.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; IMP:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR GO; GO:1902742; P:apoptotic process involved in development; IMP:UniProtKB.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IMP:UniProtKB.
DR GO; GO:0009792; P:embryo development ending in birth or egg hatching; IGI:UniProtKB.
DR GO; GO:0097194; P:execution phase of apoptosis; IDA:WormBase.
DR GO; GO:0046716; P:muscle cell cellular homeostasis; IGI:UniProtKB.
DR GO; GO:1905803; P:negative regulation of cellular response to manganese ion; IMP:UniProtKB.
DR GO; GO:1900118; P:negative regulation of execution phase of apoptosis; IMP:ComplexPortal.
DR GO; GO:1904747; P:positive regulation of apoptotic process involved in development; IMP:UniProtKB.
DR GO; GO:1905845; P:positive regulation of cellular response to gamma radiation; IMP:UniProtKB.
DR GO; GO:1901046; P:positive regulation of egg-laying behavior; IMP:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:UniProtKB.
DR GO; GO:0010954; P:positive regulation of protein processing; IMP:UniProtKB.
DR GO; GO:1905808; P:positive regulation of synapse pruning; IMP:UniProtKB.
DR GO; GO:0012501; P:programmed cell death; IMP:WormBase.
DR GO; GO:0016540; P:protein autoprocessing; IDA:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; IDA:WormBase.
DR GO; GO:0006508; P:proteolysis; IMP:UniProtKB.
DR GO; GO:0030155; P:regulation of cell adhesion; IMP:UniProtKB.
DR GO; GO:0042659; P:regulation of cell fate specification; IGI:UniProtKB.
DR GO; GO:0040034; P:regulation of development, heterochronic; IGI:UniProtKB.
DR GO; GO:0040012; P:regulation of locomotion; IGI:UniProtKB.
DR GO; GO:0031647; P:regulation of protein stability; IGI:UniProtKB.
DR GO; GO:0050807; P:regulation of synapse organization; IGI:UniProtKB.
DR GO; GO:0040028; P:regulation of vulval development; IGI:UniProtKB.
DR CDD; cd01671; CARD; 1.
DR CDD; cd00032; CASc; 1.
DR Gene3D; 3.40.50.1460; -; 1.
DR Gene3D; 1.10.533.10; Death Domain, Fas; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR029030; Caspase-like_dom_sf.
DR InterPro; IPR033139; Caspase_cys_AS.
DR InterPro; IPR016129; Caspase_his_AS.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR011600; Pept_C14_caspase.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR001309; Pept_C14_p20.
DR InterPro; IPR015917; Pept_C14A.
DR PANTHER; PTHR47901:SF7; CASPASE 2; 1.
DR PANTHER; PTHR47901; CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 18; 1.
DR Pfam; PF00619; CARD; 1.
DR Pfam; PF00656; Peptidase_C14; 1.
DR PIRSF; PIRSF038001; Caspase_ICE; 1.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00114; CARD; 1.
DR SMART; SM00115; CASc; 1.
DR SUPFAM; SSF52129; Caspase-like; 1.
DR SUPFAM; SSF47986; DEATH domain; 1.
DR PROSITE; PS50209; CARD; 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; Apoptosis; Autocatalytic cleavage; Cytoplasm;
KW Direct protein sequencing; Hydrolase; Membrane; Mitochondrion; Nucleus;
KW Protease; Reference proteome; Synapse; Thiol protease; Zymogen.
FT PROPEP 1..221
FT /evidence="ECO:0000269|PubMed:8654923"
FT /id="PRO_0000441117"
FT CHAIN 222..374
FT /note="Cell death protein 3 subunit p17"
FT /evidence="ECO:0000305"
FT /id="PRO_0000004674"
FT CHAIN 375..503
FT /note="Cell death protein 3 subunit p15"
FT /evidence="ECO:0000305"
FT /id="PRO_0000004675"
FT CHAIN 389..503
FT /note="Cell death protein 3 subunit p13"
FT /evidence="ECO:0000305"
FT /id="PRO_0000441118"
FT DOMAIN 1..91
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 106..129
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 150..179
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 389..404
FT /note="Required for interaction with ced-4"
FT /evidence="ECO:0000269|PubMed:24065769"
FT COMPBIAS 162..179
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 315
FT /evidence="ECO:0000250|UniProtKB:P29466"
FT ACT_SITE 358
FT /evidence="ECO:0000269|PubMed:24065769,
FT ECO:0000269|PubMed:8654923, ECO:0000269|PubMed:9857046"
FT SITE 221..222
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000269|PubMed:8654923"
FT SITE 374..375
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000269|PubMed:8654923"
FT SITE 388..389
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000269|PubMed:8654923"
FT MUTAGEN 27
FT /note="L->F: In n1040; increased autoprocessing in absence
FT of ced-4. Autoprocessing is blocked in presence of npp-14
FT and reduced in presence of both ced-4 and npp-14. Loss of
FT embryonic and postembryonic apoptosis resulting in survival
FT of cells in the head, ventral cord, postdeirid sensilla and
FT Q descendants in a ced-1 mutant background defective in
FT cell-corpse clearance. Apoptosis is partially restored in a
FT ced-1 (e1735) and npp-14 (sm160) double mutant background."
FT /evidence="ECO:0000269|PubMed:27723735,
FT ECO:0000269|PubMed:3955651"
FT MUTAGEN 30
FT /note="L->F: In n2439; increased autoprocessing in absence
FT of ced-4. Autoprocessing is blocked in presence of npp-14
FT and reduced in presence of both ced-4 and npp-14. Loss of
FT embryonic and postembryonic apoptosis resulting in survival
FT of cells in the anterior pharynx in a ced-1 mutant
FT background defective in cell-corpse clearance. Apoptosis is
FT partially restored in a ced-1 (e1735) and npp-14 (sm160)
FT double mutant background."
FT /evidence="ECO:0000269|PubMed:27723735"
FT MUTAGEN 51
FT /note="R->H: In n2449; normal autoprocessing. No effect on
FT embryonic and postembryonic apoptosis in a ced-1 mutant
FT background defective in cell-corpse clearance."
FT /evidence="ECO:0000269|PubMed:27723735"
FT MUTAGEN 65
FT /note="G->R: In n718; increased autoprocessing in absence
FT of ced-4. Autoprocessing is blocked in presence of npp-14
FT and reduced in presence of both ced-4 and npp-14. Loss of
FT embryonic and postembryonic apoptosis resulting in survival
FT of cells in the head, ventral cord, postdeirid sensilla and
FT Q descendants in a ced-1 mutant background defective in
FT cell-corpse clearance. Apoptosis is partially restored in a
FT ced-1 (e1735) and npp-14 (sm160) double mutant background."
FT /evidence="ECO:0000269|PubMed:27723735,
FT ECO:0000269|PubMed:3955651"
FT MUTAGEN 358
FT /note="C->S: Loss of catalytic activity. Prevents cell
FT death. Loss of processing. No effect on the interaction
FT with ced-4. Loss of interaction with octameric ced-4; when
FT associated with 391-D--D-393."
FT /evidence="ECO:0000269|PubMed:24065769,
FT ECO:0000269|PubMed:28602583, ECO:0000269|PubMed:8654923,
FT ECO:0000269|PubMed:9857046"
FT MUTAGEN 360
FT /note="G->S: In n2433; loss of catalytic activity. Loss of
FT processing. Severe reduction in the number of apoptotic
FT cells in the anterior pharynx. Loss of embryonic apoptosis
FT in a ced-1 mutant background defective in cell-corpse
FT clearance. Impaired axonal regeneration following injury.
FT Resistance to S.typhimurium-mediated killing."
FT /evidence="ECO:0000269|PubMed:11226309,
FT ECO:0000269|PubMed:22629231, ECO:0000269|PubMed:27723735,
FT ECO:0000269|PubMed:8654923"
FT MUTAGEN 366
FT /note="G->R: In ju1056; Loss of gsnl-1 cleavage. Impaired
FT elimination of presynaptic components in RME neurons in
FT adults. Abnormal accumulation of F-actin at the non-
FT eliminated transient synapses in DD neuron dorsal cord in
FT L4 larvae."
FT /evidence="ECO:0000269|PubMed:26074078"
FT MUTAGEN 391..393
FT /note="LFN->DDD: Loss of interaction with octameric ced-4;
FT when associated with S-358."
FT /evidence="ECO:0000269|PubMed:24065769"
FT MUTAGEN 449
FT /note="A->V: In n1229/n1164; severe reduction in catalytic
FT activity. Partially processed. Reduction in the number of
FT apoptotic cells in the anterior pharynx. In a ced-1 mutant
FT background, loss of embryonic and postembryonic apoptosis
FT resulting in survival of cells in the head, ventral cord,
FT postdeirid sensilla, Q descendants and cells of the
FT anterior pharynx."
FT /evidence="ECO:0000269|PubMed:3955651,
FT ECO:0000269|PubMed:8654923"
FT MUTAGEN 474
FT /note="G->R: In n2427/n2438; slight reduction in catalytic
FT activity. Almost complete processing. Slight reduction in
FT the number of apoptotic cells in the anterior pharynx.
FT Reduction is higher in a drp-1 or fis-2 mutant background.
FT Reduction in number of eggs laid. In a ced-9 (n1653) mutant
FT background, causes 60 percent embryonic lethality."
FT /evidence="ECO:0000269|PubMed:18722182,
FT ECO:0000269|PubMed:18776901, ECO:0000269|PubMed:8654923"
FT HELIX 4..12
FT /evidence="ECO:0007829|PDB:8JOL"
FT HELIX 14..17
FT /evidence="ECO:0007829|PDB:8JOL"
FT HELIX 23..32
FT /evidence="ECO:0007829|PDB:8JOL"
FT HELIX 38..45
FT /evidence="ECO:0007829|PDB:8JOL"
FT HELIX 50..63
FT /evidence="ECO:0007829|PDB:8JOL"
FT TURN 68..70
FT /evidence="ECO:0007829|PDB:8JOL"
FT HELIX 71..73
FT /evidence="ECO:0007829|PDB:8JOL"
FT HELIX 74..77
FT /evidence="ECO:0007829|PDB:8JOL"
FT HELIX 81..91
FT /evidence="ECO:0007829|PDB:8JOL"
FT HELIX 214..216
FT /evidence="ECO:0007829|PDB:4M9R"
FT HELIX 222..228
FT /evidence="ECO:0007829|PDB:4M9R"
FT TURN 231..233
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 243..249
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 254..256
FT /evidence="ECO:0007829|PDB:4M9R"
FT HELIX 262..275
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 278..285
FT /evidence="ECO:0007829|PDB:4M9R"
FT HELIX 288..298
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 306..317
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 320..322
FT /evidence="ECO:0007829|PDB:4M9R"
FT HELIX 331..336
FT /evidence="ECO:0007829|PDB:4M9R"
FT TURN 340..342
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 351..357
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 360..362
FT /evidence="ECO:0007829|PDB:4M9R"
FT TURN 411..414
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 415..421
FT /evidence="ECO:0007829|PDB:4M9R"
FT TURN 431..433
FT /evidence="ECO:0007829|PDB:4M9R"
FT HELIX 436..448
FT /evidence="ECO:0007829|PDB:4M9R"
FT TURN 449..451
FT /evidence="ECO:0007829|PDB:4M9R"
FT HELIX 454..468
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 471..473
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 476..478
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 483..486
FT /evidence="ECO:0007829|PDB:4M9R"
FT STRAND 489..491
FT /evidence="ECO:0007829|PDB:4M9R"
SQ SEQUENCE 503 AA; 56617 MW; 722D5831F94DAA69 CRC64;
MMRQDRRSLL ERNIMMFSSH LKVDEILEVL IAKQVLNSDN GDMINSCGTV REKRREIVKA
VQRRGDVAFD AFYDALRSTG HEGLAEVLEP LARSVDSNAV EFECPMSPAS HRRSRALSPA
GYTSPTRVHR DSVSSVSSFT SYQDIYSRAR SRSRSRALHS SDRHNYSSPP VNAFPSQPSS
ANSSFTGCSS LGYSSSRNRS FSKASGPTQY IFHEEDMNFV DAPTISRVFD EKTMYRNFSS
PRGMCLIINN EHFEQMPTRN GTKADKDNLT NLFRCMGYTV ICKDNLTGRG MLLTIRDFAK
HESHGDSAIL VILSHGEENV IIGVDDIPIS THEIYDLLNA ANAPRLANKP KIVFVQACRG
ERRDNGFPVL DSVDGVPAFL RRGWDNRDGP LFNFLGCVRP QVQQVWRKKP SQADILIAYA
TTAQYVSWRN SARGSWFIQA VCEVFSTHAK DMDVVELLTE VNKKVACGFQ TSQGSNILKQ
MPEMTSRLLK KFYFWPEARN SAV
//
