| IED ID | IndEnz0002014254 |
| Enzyme Type ID | protease014254 |
| Protein Name |
Cell death protein 3 EC 3.4.22.60 Caspase ced-3 Cleaved into: Cell death protein 3 subunit p17; Cell death protein 3 subunit p15; Cell death protein 3 subunit p13 |
| Gene Name | ced-3 C48D1.2 |
| Organism | Caenorhabditis elegans |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Protostomia Ecdysozoa Nematoda (roundworms) Chromadorea Rhabditida Rhabditina Rhabditomorpha Rhabditoidea Rhabditidae Peloderinae Caenorhabditis Caenorhabditis elegans |
| Enzyme Sequence | MMRQDRRSLLERNIMMFSSHLKVDEILEVLIAKQVLNSDNGDMINSCGTVREKRREIVKAVQRRGDVAFDAFYDALRSTGHEGLAEVLEPLARSVDSNAVEFECPMSPASHRRSRALSPAGYTSPTRVHRDSVSSVSSFTSYQDIYSRARSRSRSRALHSSDRHNYSSPPVNAFPSQPSSANSSFTGCSSLGYSSSRNRSFSKASGPTQYIFHEEDMNFVDAPTISRVFDEKTMYRNFSSPRGMCLIINNEHFEQMPTRNGTKADKDNLTNLFRCMGYTVICKDNLTGRGMLLTIRDFAKHESHGDSAILVILSHGEENVIIGVDDIPISTHEIYDLLNAANAPRLANKPKIVFVQACRGERRDNGFPVLDSVDGVPAFLRRGWDNRDGPLFNFLGCVRPQVQQVWRKKPSQADILIAYATTAQYVSWRNSARGSWFIQAVCEVFSTHAKDMDVVELLTEVNKKVACGFQTSQGSNILKQMPEMTSRLLKKFYFWPEARNSAV |
| Enzyme Length | 503 |
| Uniprot Accession Number | P42573 |
| Absorption | |
| Active Site | ACT_SITE 315; /evidence="ECO:0000250|UniProtKB:P29466"; ACT_SITE 358; /evidence="ECO:0000269|PubMed:24065769, ECO:0000269|PubMed:8654923, ECO:0000269|PubMed:9857046" |
| Activity Regulation | ACTIVITY REGULATION: Octomeric ced-4 activates zymogen autoprocessing and enhances activity of processed ced-3 (PubMed:18776901, PubMed:19575016, PubMed:27723735, PubMed:24065769, PubMed:20434985). Zymogen autoactivation is inhibited by csp-3 (PubMed:18776901). csp-3 has no effect on active ced-3 (PubMed:18776901). Zymogen autoactivation is inhibited by csp-2 (PubMed:19575016). Inhibited by cysteine protease inhibitor iodoacetic acid (CH3COOI) (PubMed:8654923, PubMed:9857046, PubMed:18776901, PubMed:19575016, PubMed:27723735). Inhibited by benzyloxycarbonyl-DEVD-fluoro-methyl ketone (zDEVD-fmk) (PubMed:8654923, PubMed:9857046, PubMed:25432023). Inhibited by benzyloxycarbonyl-VAD-fluoro-methyl ketone (zVAD-fmk) (PubMed:17371877, PubMed:21909434). Not inhibited by N-[N-(L-3-transcarboxirane-2-carbonyl)-leucyl]-agmatine (E-64) or by the serine and cysteine protease inhibitor L-1-chloro-3-[4-to-osylamido]-7-amino-2-heptanone (TLCK) (PubMed:8654923, PubMed:9857046). {ECO:0000269|PubMed:17371877, ECO:0000269|PubMed:18776901, ECO:0000269|PubMed:19575016, ECO:0000269|PubMed:20434985, ECO:0000269|PubMed:21909434, ECO:0000269|PubMed:24065769, ECO:0000269|PubMed:25432023, ECO:0000269|PubMed:27723735, ECO:0000269|PubMed:8654923, ECO:0000269|PubMed:9857046}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Asp-Glu-Val-Asp-|-.; EC=3.4.22.60; Evidence={ECO:0000269|PubMed:10764728, ECO:0000269|PubMed:17371877, ECO:0000269|PubMed:18722182, ECO:0000269|PubMed:18776901, ECO:0000269|PubMed:19575016, ECO:0000269|PubMed:20223951, ECO:0000269|PubMed:21909434, ECO:0000269|PubMed:24065769, ECO:0000269|PubMed:24225442, ECO:0000269|PubMed:25383666, ECO:0000269|PubMed:25432023, ECO:0000269|PubMed:27723735, ECO:0000269|PubMed:8654923, ECO:0000269|PubMed:9857046, ECO:0000305|PubMed:26074078}; |
| DNA Binding | |
| EC Number | 3.4.22.60 |
| Enzyme Function | FUNCTION: Acts as a cysteine protease in controlling programmed cell death (apoptosis) by proteolytically activating or inactivating a wide range of substrates (PubMed:8654923, PubMed:3955651, PubMed:18722182, PubMed:26074078, PubMed:27723735). Component of the egl-1, ced-9, ced-4 and ced-3 apoptotic signaling cascade required for the initiation of programmed cell death in cells fated to die during embryonic and postembryonic development (PubMed:3955651, PubMed:17329362, PubMed:25432023, PubMed:27723735). During oogenesis, required for germline apoptosis downstream of ced-9 and ced-4 but independently of egl-1 (PubMed:9927601). By cleaving and activating ced-8, promotes phosphatidylserine exposure on the surface of apoptotic cells; phosphatidylserine is a specific marker only present at the surface of apoptotic cells and acts as a specific signal for engulfment (PubMed:24225442). By cleaving and converting dcr-1 into a deoxyribonuclease (DNase), promotes apoptotic chromosomal DNA fragmentation (PubMed:20223951). By cleaving mitochondrial fission protein drp-1, may regulate the removal of mitochondria during apoptosis (PubMed:18722182). During germline apoptosis, cleaves translation initiation factor ifg-1 (isoform p170) promoting cap-independent translation (PubMed:21909434). During male tail morphogenesis, promotes apoptosis of the tail-spike cell downstream of ced-4 but independently of egl-1 and ced-9 (PubMed:17329362). By cleaving cnt-1, prevents the activation of the prosurvival akt-1/2 signaling pathway and thus promotes apoptosis (PubMed:25383666). Downstream of ced-4, may play a role in sex-specific cell apoptosis by cleaving sex-determining protein fem-1 (PubMed:10764728). May regulate germline apoptosis in response to DNA damage, probably downstream of let-60/ras and mpk-1 pathway (PubMed:21901106). Cleaves ced-9 in vitro (PubMed:17371877, PubMed:18776901, PubMed:19575016, PubMed:25432023, PubMed:27723735). Cleaves csp-2 isoform b resulting in the removal of the propeptide and the generation of csp-2 subunit p31 in vitro (PubMed:9857046). Independently of its apoptotic role has additional functions. Probably by cleaving and thereby activating actin-severing protein gsnl-1, required for the elimination of transient presynaptic components during larval development downstream of egl-1, ced-9 and ced-4 pathway (PubMed:26074078). Together with ain-1, a component of the miRNA-induced-silencing complex (miRISC), regulates temporal cell fate patterning during larval development (PubMed:25432023). In complex with ubr-1, which is E3 ubiquitin-protein ligase and component of the N-end rule pathway, acts in seam cell fate patterning during larval development by cleaving the heterochronic protein lin-28, and promoting its degradation (PubMed:25432023, PubMed:28602583). Also cleaves heterochronic protein lin-14 and exonuclease disl-2 in vitro (PubMed:25432023). Downstream of calreticulin crt-1 and ced-4 and independently of egl-1 and ced-9, plays a role in the initial steps of axonal regrowth following axotomy (PubMed:22629231). Cleaves 14-3-3-like protein ftt-2, tubulin tbb-2 and calreticulin crt-1 in vitro (PubMed:17371877). Plays also a role in resistance to S.typhimurium-mediated infection (PubMed:11226309). {ECO:0000269|PubMed:10764728, ECO:0000269|PubMed:11226309, ECO:0000269|PubMed:17329362, ECO:0000269|PubMed:17371877, ECO:0000269|PubMed:18722182, ECO:0000269|PubMed:18776901, ECO:0000269|PubMed:19575016, ECO:0000269|PubMed:20223951, ECO:0000269|PubMed:21901106, ECO:0000269|PubMed:21909434, ECO:0000269|PubMed:22629231, ECO:0000269|PubMed:24225442, ECO:0000269|PubMed:25383666, ECO:0000269|PubMed:25432023, ECO:0000269|PubMed:26074078, ECO:0000269|PubMed:27723735, ECO:0000269|PubMed:28602583, ECO:0000269|PubMed:3955651, ECO:0000269|PubMed:8654923, ECO:0000269|PubMed:9857046, ECO:0000269|PubMed:9927601}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Beta strand (12); Chain (3); Compositional bias (1); Domain (1); Helix (7); Mutagenesis (10); Propeptide (1); Region (3); Site (3); Turn (5) |
| Keywords | 3D-structure;Apoptosis;Autocatalytic cleavage;Cell junction;Cytoplasm;Direct protein sequencing;Hydrolase;Membrane;Mitochondrion;Nucleus;Protease;Reference proteome;Synapse;Thiol protease;Zymogen |
| Interact With | Itself; P30429; P30429-2; P41958; G5ECW5 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Nucleus membrane {ECO:0000269|PubMed:27723735}. Perikaryon {ECO:0000269|PubMed:26074078}. Cell junction, synapse {ECO:0000269|PubMed:26074078}. Mitochondrion {ECO:0000269|PubMed:26074078}. Cytoplasm {ECO:0000269|PubMed:27723735}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:27723735}. Note=Colocalizes with nucleoporin npp-14 to the perinuclear region in germ cells (PubMed:27723735). Becomes diffused in the cytoplasm in apoptotic germ cells (PubMed:27723735). Localizes to axonal mitochondria and synapses of DD motor neurons (PubMed:26074078). Synaptic localization is dependent on axonal mitochondria (PubMed:26074078). {ECO:0000269|PubMed:26074078, ECO:0000269|PubMed:27723735}. |
| Modified Residue | |
| Post Translational Modification | PTM: Autocatalytic cleavage removes the propeptide and generates the catalytic subunit p17 and two non-catalytic subunits p15 and p13; autoproteolysis is induced by ced-4 oligomer (PubMed:8654923, PubMed:9857046, PubMed:17371877, PubMed:18776901, PubMed:19575016, PubMed:27723735, PubMed:20434985). Cleaved by caspase csp-1 probably at Asp-144 and Asp-374 (PubMed:9857046). {ECO:0000269|PubMed:18776901, ECO:0000269|PubMed:19575016, ECO:0000269|PubMed:20434985, ECO:0000269|PubMed:27723735, ECO:0000269|PubMed:8654923, ECO:0000269|PubMed:9857046}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (5) |
| Cross Reference PDB | 4M9R; 4M9S; 4M9X; 4M9Y; 4M9Z; |
| Mapped Pubmed ID | 10581274; 10778742; 11231151; 11449279; 11595183; 11696333; 11779177; 12840007; 15055582; 15122042; 15238520; 15543163; 15744306; 16005300; 16208361; 16294007; 16537504; 16788064; 16938876; 17021039; 17081157; 17237514; 17411345; 17540571; 17717195; 17996738; 18319623; 18425118; 18832646; 19168360; 19497412; 19667176; 20150917; 20970339; 21085631; 21177967; 21490059; 21502138; 21527776; 21529718; 21596567; 22267497; 22286215; 22560298; 22590572; 22801495; 22918439; 23505386; 23721876; 23800452; 23832114; 24030151; 24285704; 24323044; 24445071; 24884423; 25487147; 25762526; 26657541; 26912668; 27185172; 27493871; 27516615; 27798844; 27842058; 28659600; 28733033; 29346364; 30194072; 6593563; 8598288; 8631956; 9027312; 9109415; 9210374; 9261161; 9285582; 9384385; 9604928; 9651369; 9721101; 9824163; |
| Motif | |
| Gene Encoded By | |
| Mass | 56,617 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |