CED-3 (Caenorhabditis elegans)
Description [+]
- Synonyms: CED-3
- Species: Metazoa;Bilateria;Ecdysozoa;Nematoda; Caenorhabditis elegans
- Short gene description: The ced-3 gene encodes a protease required for apoptosis. [Source: WormBase]
- Family: CASPASE
- Process: apoptosis,
- Pathways:
- Criteria: manually curated
- Curator comment:
- Human ortholog(s): CASP6 CASP10 CASP3 CASP8 CASP7 CASP9
- WIKI: CED-3-C_elegans
References [+]
- The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease.
- Xue D, Shaham S, Horvitz HR
- The Caenorhabditis elegans cell-death gene ced-3 encodes a protein similar to mammalian interleukin-1beta-converting enzyme (ICE), a cysteine protease implicated in mammalian apoptosis. We show that the full-length CED-3 protein undergoes proteolytic activation to generate a CED-3 cysteine protease and that CED-3 protease activity is required for killing cells by programmed cell death in C. elegans. We developed an easy and general method for the purification of CED-3/ICE-like proteases and used this method to facilitate a comparison of the substrate specificities of four different purified cysteine proteases. We found that in its substrate preferences CED-3 was more similar to the mammalian CPP32 protease than to mammalian ICE or NEDD2/ICH-1 protease. Our results suggest that different mammalian CED-3/ICE-like proteases may have distinct roles in mammalian apoptosis and that CPP32 is a candidate for being a mammalian functional equivalent of CED-3. Genes Dev. 1996 May 1;10(9):1073-83.
- References from Human ortholog(s):
- In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains.
- Fernandes-Alnemri T, Armstrong RC, Krebs J, Srinivasula SM, Wang L, Bullrich F, Fritz LC, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES
- Emerging evidence suggests that an amplifiable protease cascade consisting of multiple aspartate specific cysteine proteases (ASCPs) is responsible for the apoptotic changes observed in mammalian cells undergoing programmed cell death. Here we describe the cloning of two novel ASCPs from human Jurkat T-lymphocytes. Like other ASCPs, the new proteases, named Mch4 and Mch5, are derived from single chain proenzymes. However, their putative active sites contain a QACQG pentapeptide instead of the QACRG present in ail known ASCPs. Also, their N termini contain FADD-like death effector domains, suggesting possible interaction with FADD. Expression of Mch4 in Escherichia coli produced an active protease that, like other ASCPs, was potently inhibited (Kj = 14 nM) by the tetrapeptide aldehyde DEVD-CHO. Interestingly, both Mch4 and the serine protease granzyme B cleave recombinant proCPP32 and proMch3 at a conserved IXXD-S sequence to produce the large and small subunits of the active proteases. Granzyme B also cleaves proMch4 at a homologous IXXD-A processing sequence to produce mature Mch4. These observations suggest that CPP32 and Mch3 are targets of mature Mch4 protease in apoptotic cells. The presence of the FADD-like domains in Mch4 and Mch5 suggests a role for these proteases in the Fas-apoptotic pathway. In addition, these proteases could participate in the granzyme B apoptotic pathways. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7464-9.
- CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme.
- Fernandes-Alnemri T, Litwack G, Alnemri ES
- We have cloned a novel apoptotic gene from human Jurkat T-lymphocytes. The new gene encodes a 32-kDa putative cysteine protease (CPP32) with significant homology to Caenorhabditis elegans cell death protein Ced-3, mammalian interleukin-1 beta-converting enzyme (ICE), and the product of the mouse nedd2 gene. The CPP32 transcript is highly expressed and most abundant in cell lines of lymphocytic origin. Overexpression of CPP32 or ICE in Sf9 insect cells resulted in apoptosis. In addition, coexpression of recombinant p20 and p11 derived from the parental full-length CPP32 sequence resulted in apoptosis in Sf9 cells. Our data suggest that similar to ICE, CPP32 is made of two subunits, p20 and p11, which form the active CPP32 complex. The apoptotic activity of CPP32 and its high expression in lymphocytes suggest that CPP32 is an important mediator of apoptosis in the immune system. J Biol Chem. 1994 Dec 9;269(49):30761-4.
- Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family.
- Fernandes-Alnemri T, Litwack G, Alnemri ES
- We have developed a PCR approach to clone new apoptotic Ced-3/Ice-like cysteine protease genes. This approach uses degenerate oligonucleotides encoding the highly conserved pentapeptides QACRG and GSWFI that are present in all known apoptotic cysteine proteases. Using this approach, we have cloned a novel apoptotic gene from human Jurkat T lymphocytes. The new gene encodes a approximately 34-kilodalton protein that is highly homologous to human CPP32, Caenorhabditis elegans cell death protein CED-3, mammalian Ich-1 (Nedd2), and mammalian interleukin-1 beta converting enzyme. Because of its high homology to the C. elegans Ced-3 gene, we named the new gene mammalian Ced-3 homologue Mch2. Two Mch2 transcripts (Mch2 alpha, 1.7 kb; Mch2 beta, 1.4 kb) were detected in Jurkat T lymphocytes and other cell lines. We believe that the Mch2 alpha transcript encodes the full-length Mch2, whereas the Mch2 beta transcript encodes a shorter Mch2 isoform, probably as a result of alternative splicing. Like interleukin-1 beta converting enzyme and CPP32, recombinant Mch2 alpha, but not Mch2 beta, possesses protease activity, as determined by its ability to cleave the fluorogenic peptide DEVD-AMC. CPP32 and Mch2 alpha can also cleave poly(ADP-ribose) polymerase in vitro, suggesting that these enzymes participate in poly(ADP-ribose) polymerase cleavage observed during cellular apoptosis. In addition, overexpression of recombinant Mch2 alpha, but not Mch2 beta, induces apoptosis in Sf9 insect cells. Our data suggest that Mch2 is a Ced-3/interleukin-1 beta converting enzyme-like cysteine protease and could be another important mediator of apoptosis in mammalian cells. Cancer Res. 1995 Jul 1;55(13):2737-42.
- Mch3, a novel human apoptotic cysteine protease highly related to CPP32.
- Fernandes-Alnemri T, Takahashi A, Armstrong R, Krebs J, Fritz L, Tomaselli KJ, Wang L, Yu Z, Croce CM, Salveson G, et al.
- Recent evidence suggests that mammalian cysteine proteases related to Caenorhabditis elegans CED-3 are key components of mammalian programmed cell death or apoptosis. We have shown recently that the CPP32 and Mch2 alpha cysteine proteases cleave the apoptotic markers poly(ADP-ribose) polymerase (PARP) and lamins, respectively. Here we report the cloning of a new Ced-3/interleukin 1 beta-converting enzyme-related gene, designated Mch3, that encodes a protein with the highest degree of homology to CPP32 compared to other family members. An alternatively spliced isoform, named Mch3 beta, was also identified. Bacterially expressed recombinant Mch3 has intrinsic autocatalytic/autoactivation activity. The specific activity of Mch3 alpha toward the peptide substrate DEVD-7-amino-4-methylcoumarin and PARP resembles that of CPP32. Like interleukin 1 beta-converting enzyme and CPP32, the active Mch3 alpha is made of two subunits derived from a precursor (proMch3 alpha). It was of interest that recombinant CPP32-p17 subunit can form an active heteromeric enzyme complex with recombinant Mch3 alpha-p12 subunit and vice versa, as determined by the ability of the heteromeric complexes to induce apoptosis in Sf9 cells. These data suggest that proMch3 alpha and proCPP32 can interact to form an active Mch3 alpha/CPP32 heteromeric complex. We also provide evidence that CPP32 can efficiently cleave proMch3 alpha, but not the opposite, suggesting that Mch3 alpha activation in vivo may depend in part on CPP32 activity. The high degree of conservation in structure and specific activity and the coexistence of Mch3 alpha and CPP32 in the same cell suggests that the PARP cleavage activity observed during apoptosis cannot solely be attributed to CPP32 but could also be an activity of Mch3 alpha. Cancer Res. 1995 Dec 15;55(24):6045-52.
- Identification and mapping of Casp7, a cysteine protease resembling CPP32 beta, interleukin-1 beta converting enzyme, and CED-3.
- Juan TS, McNiece IK, Argento JM, Jenkins NA, Gilbert DJ, Copeland NG, Fletcher FA
- Cloning of interleukin-1 beta converting enzyme (ICE) and Caenorhabditis elegans death protein CED-3 revealed the structural and functional homology between these two proteases. It also suggested the involvement of ICE-like cysteine proteases in apoptosis. Several CED-3- and ICE-like cysteine proteases have been described, including Nedd2/Ich-1, CPP32 beta, Tx, ICErel3, and Mch2. We have previously described a mouse ortholog of cysteine protease CPP32 beta that shares strong homology with ICE and CED-3. Here, we describe the cloning of mouse and human Casp7, another member of this family of cysteine proteases. Mouse Casp7 encodes a putative 340-amino-acid polypeptide that contains all the known conserved residues required for protease function, including the QACRG sequence, aspartic acid residues for internal cleavage sites, and the residues required for substrate binding. Three RNA variants of human Casp7 were also cloned. Amino acid sequence analysis indicated that Casp7 shared high homology with CPP32 beta/Casp3 and Mch2/Casp6. Northern blot analysis demonstrated that a 2.6-kb Casp7 mRNA was expressed in various tissues except brain. Mouse interspecific backcross mapping allowed localization of Casp7 to the distal region of mouse chromosome 19, linked to Mxi1, Adra2a, and Aop1. Genomics. 1997 Feb 15;40(1):86-93.
- Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.
- Boldin MP, Goncharov TM, Goltsev YV, Wallach D
- Fas/APO-1 and p55 tumor necrosis factor (TNF) receptor (p55-R) activate cellular mechanisms that result in cell death. Upon activation of these receptors, Fas/APO-1 binds a protein called MORT1 (or FADD) and p55-R binds a protein called TRADD. MORT1 and TRADD can also bind to each other. We have cloned a novel protein, MACH, that binds to MORT1. This protein exists in multiple isoforms, some of which contain a region that has proteolytic activity and shows marked sequence homology to proteases of the ICE/CED-3 family. Cellular expression of the proteolytic MACH isoforms results in cell death. Expression of MACH isoforms that contain an incomplete ICE/CED-3 region provides effective protection against the cytotoxicity induced by Fas/APO-1 or p55-R triggering. These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades. Cell. 1996 Jun 14;85(6):803-15.
- The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32.
- Srinivasula SM, Fernandes-Alnemri T, Zangrilli J, Robertson N, Armstrong RC, Wang L, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES
- Recent evidence suggests that CPP32 is an essential component of an aspartate-specific cysteine protease (ASCP) cascade responsible for apoptosis execution in mammalian cells. Activation of CPP32 could lead to activation of other downstream ASCPs, resulting in late morphological changes such as lamin cleavage and DNA fragmentation, observed in cells undergoing apoptosis. Here we describe the identification and cloning of a novel human ASCP named Mch6 from Jurkat T lymphocytes. We demonstrate that the pro-enzymes of Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for mature CPP32. Site-directed mutagenesis revealed that CPP32 processes pro-Mch6 preferentially at Asp330 to generate two subunits of molecular masses 37 kDa (p37) and 10 kDa (p10). However, CPP32 processes pro-Mch2alpha at three aspartate processing sites (Asp23, Asp179, and Asp193) to produce the large (p18) and small (p11) subunits of the mature Mch2alpha enzyme. The CPP32-processed Mch2alpha is capable of cleaving the VEIDN lamin cleavage site, indicating that CPP32 can, in fact, activate pro-Mch2alpha. Granzyme B at a concentration that allows processing and activation of CPP32 failed to process pro-Mch2alpha. However, incubation of pro-Mch2alpha with granzyme B in the presence of a cellular extract containing pro-CPP32 resulted in activation of pro-CPP32 and subsequent processing of pro-Mch2alpha. Interestingly, granzyme B can also process pro-Mch6 but at a site N-terminal to that cleaved by CPP32. These data suggest that Mch2alpha and Mch6 are downstream proteases activated in CPP32- and granzyme B-mediated apoptosis. This is the first demonstration of a protease cascade involving granzyme B, CPP32, Mch2alpha, and Mch6 and evidence that the lamin-cleaving enzyme Mch2 is a target of mature CPP32. J Biol Chem. 1996 Oct 25;271(43):27099-106.
Structure & Sequence [+]
Pfam domains:
(Pfam is a large collection of protein families.)
| Source | Domain Name | Start | End |
|---|---|---|---|
| PFAM A | CARD | 7 | 91 |
| PFAM A | Peptidase_C14 | 243 | 494 |
Protein sequence [+]
ced-3 | Caenorhabditis elegans | 6239 | length:503
MMRQDRRSLLERNIMMFSSHLKVDEILEVLIAKQVLNSDNGDMINSCGTVREKRREIVKA
VQRRGDVAFDAFYDALRSTGHEGLAEVLEPLARSVDSNAVEFECPMSPASHRRSRALSPA
GYTSPTRVHRDSVSSVSSFTSYQDIYSRARSRSRSRALHSSDRHNYSSPPVNAFPSQPSS
ANSSFTGCSSLGYSSSRNRSFSKASGPTQYIFHEEDMNFVDAPTISRVFDEKTMYRNFSS
PRGMCLIINNEHFEQMPTRNGTKADKDNLTNLFRCMGYTVICKDNLTGRGMLLTIRDFAK
HESHGDSAILVILSHGEENVIIGVDDIPISTHEIYDLLNAANAPRLANKPKIVFVQACRG
ERRDNGFPVLDSVDGVPAFLRRGWDNRDGPLFNFLGCVRPQVQQVWRKKPSQADILIAYA
TTAQYVSWRNSARGSWFIQAVCEVFSTHAKDMDVVELLTEVNKKVACGFQTSQGSNILKQ
MPEMTSRLLKKFYFWPEARNSAV
VQRRGDVAFDAFYDALRSTGHEGLAEVLEPLARSVDSNAVEFECPMSPASHRRSRALSPA
GYTSPTRVHRDSVSSVSSFTSYQDIYSRARSRSRSRALHSSDRHNYSSPPVNAFPSQPSS
ANSSFTGCSSLGYSSSRNRSFSKASGPTQYIFHEEDMNFVDAPTISRVFDEKTMYRNFSS
PRGMCLIINNEHFEQMPTRNGTKADKDNLTNLFRCMGYTVICKDNLTGRGMLLTIRDFAK
HESHGDSAILVILSHGEENVIIGVDDIPISTHEIYDLLNAANAPRLANKPKIVFVQACRG
ERRDNGFPVLDSVDGVPAFLRRGWDNRDGPLFNFLGCVRPQVQQVWRKKPSQADILIAYA
TTAQYVSWRNSARGSWFIQAVCEVFSTHAKDMDVVELLTEVNKKVACGFQTSQGSNILKQ
MPEMTSRLLKKFYFWPEARNSAV
Structure links:
Evolution [+]
View protein alignment and tree with Jalview:
Explore tree at phylomeDB: Click here.
Homologs list [+]
| Name | Relationship | Species |
|---|---|---|
| A_aegypti_AAEL003444-PA | orthology | Aedes |
| CASPS7 | orthology | Anopheles |
| CASPS6 | orthology | Anopheles |
| CASPS5 | orthology | Anopheles |
| CASPS4 | orthology | Anopheles |
| Q90WU0_CHICK | orthology | Chicken |
| NP_001038154.1 | orthology | Chicken |
| NP_989923.1 | orthology | Chicken |
| CASP7 | orthology | Chicken |
| NP_990056.1 | orthology | Chicken |
| NP_990057.1 | orthology | Chicken |
| CASP7 | orthology | Chimpanzee |
| CASP8 | orthology | Chimpanzee |
| CASP6 | orthology | Chimpanzee |
| CASP3_PANTR | orthology | Chimpanzee |
| CASP9 | orthology | Chimpanzee |
| C_intestinalis_ENSCINP00000003204 | orthology | Ciona |
| C_intestinalis_ENSCINP00000024485 | orthology | Ciona |
| C_intestinalis_ENSCINP00000025743 | orthology | Ciona |
| NP_001039435.1 | orthology | Cow |
| IPI00704513.4 | orthology | Cow |
| IPI00689801.3 | orthology | Cow |
| CASP6_BOVIN | orthology | Cow |
| CASP3_BOVIN | orthology | Cow |
| CASP7 | orthology | Dog |
| CASP6 | orthology | Dog |
| Q38JA9_CANFA | orthology | Dog |
| CASP10 | orthology | Dog |
| Q45T68_CANFA | orthology | Dog |
| CASP3_CANFA | orthology | Dog |
| Dcp-1 | orthology | Fly |
| Ice | orthology | Fly |
| T_rubripes_ENSTRUP00000044662 | orthology | Fugu |
| CASP9 | orthology | Fugu |
| CASP6 | orthology | Fugu |
| T_rubripes_ENSTRUP00000024164 | orthology | Fugu |
| T_rubripes_ENSTRUP00000024467 | orthology | Fugu |
| CASP7 | orthology | Fugu |
| NP_001027871.1 | orthology | Fugu |
| CASP9 | orthology | Gasterosteus |
| CASP7 | orthology | Gasterosteus |
| G_aculeatus_ENSGACP00000016969 | orthology | Gasterosteus |
| G_aculeatus_ENSGACP00000016983 | orthology | Gasterosteus |
| CASP3 (4 of 4) | orthology | Gasterosteus |
| CASP6 | orthology | Gasterosteus |
| CASP3 (3 of 4) | orthology | Gasterosteus |
| CASP3 (2 of 4) | orthology | Gasterosteus |
| CASP3 (1 of 4) | orthology | Gasterosteus |
| CASP8 | orthology | Gorilla |
| CASP7 | orthology | Gorilla |
| CASP9 | orthology | Horse |
| Q3S2Z5_HORSE | orthology | Horse |
| CASP10 | orthology | Horse |
| CASP8 | orthology | Horse |
| CASP6 | orthology | Horse |
| CASP7 | orthology | Horse |
| CASP6 | orthology | Human |
| CASP10 | orthology | Human |
| CASP3 | orthology | Human |
| CASP8 | orthology | Human |
| CASP7 | orthology | Human |
| CASP9 | orthology | Human |
| CASP10 | orthology | Lyzard |
| CASP3 | orthology | Lyzard |
| CASP7 | orthology | Lyzard |
| CASP6 | orthology | Lyzard |
| CASP7 | orthology | Macaca |
| Q8SPU2_MACMU | orthology | Macaca |
| CASP8 | orthology | Macaca |
| CASP9 | orthology | Macaca |
| CASP9 | orthology | Medaka |
| Q8JIS9_ORYLA | orthology | Medaka |
| Q8JIS8_ORYLA | orthology | Medaka |
| NP_001033059.1 | orthology | Monodelphis |
| NP_001033061.1 | orthology | Monodelphis |
| CASP6 | orthology | Monodelphis |
| CASP8 | orthology | Monodelphis |
| CASP10 | orthology | Monodelphis |
| CASP9 | orthology | Monodelphis |
| Casp7 | orthology | Mouse |
| Casp8 | orthology | Mouse |
| Casp6 | orthology | Mouse |
| Casp9 | orthology | Mouse |
| Casp3 | orthology | Mouse |
| CASP6 | orthology | Orangutan |
| CASP3 | orthology | Orangutan |
| CASP9 | orthology | Orangutan |
| CASP7 | orthology | Orangutan |
| Q5RB11_PONPY | orthology | Orangutan |
| Q5RCR7_PONPY | orthology | Orangutan |
| CASP3 | orthology | Ornithorhynchus |
| CASP7 | orthology | Ornithorhynchus |
| CASP6 | orthology | Ornithorhynchus |
| CASP8 | orthology | Ornithorhynchus |
| CASP9 | orthology | Ornithorhynchus |
| CASP8 | orthology | Rabbit |
| CASP7 | orthology | Rabbit |
| Casp6 | orthology | Rat |
| Casp3 | orthology | Rat |
| Casp8 | orthology | Rat |
| Casp9 | orthology | Rat |
| Casp7 | orthology | Rat |
| T_nigroviridis_ENSTNIP00000001216 | orthology | Tetraodon |
| CASP3 | orthology | Tetraodon |
| CASP9 | orthology | Tetraodon |
| CASP7 | orthology | Tetraodon |
| CASP3 | orthology | Xenopus |
| casp10 | orthology | Xenopus |
| casp7 | orthology | Xenopus |
| casp6 | orthology | Xenopus |
| T_guttata_ENSTGUP00000004278 | orthology | Zebra finch |
| CASP3 | orthology | Zebra finch |
| CASP8 | orthology | Zebra finch |
| T_guttata_ENSTGUP00000011206 | orthology | Zebra finch |
| CASP9 | orthology | Zebra finch |
| casp3a | orthology | Zebrafish |
| casp7 | orthology | Zebrafish |
| casp8l2 | orthology | Zebrafish |
| D_rerio_ENSDARP00000047019 | orthology | Zebrafish |
| NP_001077331.1 | orthology | Zebrafish |
| casp3b | orthology | Zebrafish |
| LOC100000522 | orthology | Zebrafish |
| A2BGE2_DANRE | orthology | Zebrafish |
| LOC795066 | orthology | Zebrafish |
| NP_990255.1 | paralogy | Chicken |
| CASP2_CHICK | paralogy | Chicken |
| CASP2 | paralogy | Chimpanzee |
| C_intestinalis_ENSCINP00000002956 | paralogy | Ciona |
| C_intestinalis_ENSCINP00000007986 | paralogy | Ciona |
| IPI00707783.1 | paralogy | Cow |
| CASP2 | paralogy | Dog |
| CASP2 | paralogy | Fugu |
| CASP2 | paralogy | Gasterosteus |
| CASP2 | paralogy | Horse |
| CASP2 | paralogy | Human |
| CASP2 | paralogy | Lyzard |
| Q8SPP8_MACMU | paralogy | Macaca |
| CASP2 | paralogy | Medaka |
| CASP2 | paralogy | Monodelphis |
| Casp2 | paralogy | Mouse |
| CASP2 | paralogy | Orangutan |
| CASP2 | paralogy | Ornithorhynchus |
| Casp2 | paralogy | Rat |
| CASP2 | paralogy | Tetraodon |
| csp-1 | paralogy | Worm |
| csp-2 | paralogy | Worm |
| CASP2 | paralogy | Xenopus |
| T_guttata_ENSTGUP00000013612 | paralogy | Zebra finch |
| casp2 | paralogy | Zebrafish |
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