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Protein

Cell death protein 3

Gene

ced-3

Organism
Caenorhabditis elegans
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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). Acts in cell fate patterning by cleaving heterochronic protein lin-28, likely promoting its degradation (PubMed:25432023). 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 calrecticulin crt-1 in vitro (PubMed:17371877). Plays also a role in resistance to S.typhimurium-mediated infection (PubMed:11226309).20 Publications

Catalytic activityi

Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Asp-Glu-Val-Asp-|-.1 Publication14 Publications

Enzyme regulationi

Octameric 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).10 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei315By similarity1
Active sitei3583 Publications1

GO - Molecular functioni

  • cysteine-type endopeptidase activator activity involved in apoptotic process Source: UniProtKB
  • cysteine-type endopeptidase activity Source: WormBase
  • cysteine-type endopeptidase activity involved in execution phase of apoptosis Source: WormBase
  • endopeptidase activity Source: WormBase
  • identical protein binding Source: IntAct

GO - Biological processi

  • actin filament depolymerization Source: UniProtKB
  • activation of cysteine-type endopeptidase activity Source: UniProtKB
  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • apoptotic process Source: WormBase
  • apoptotic process involved in development Source: UniProtKB
  • embryo development ending in birth or egg hatching Source: WormBase
  • execution phase of apoptosis Source: WormBase
  • negative regulation of cellular response to manganese ion Source: UniProtKB
  • positive regulation of apoptotic process involved in development Source: UniProtKB
  • positive regulation of cellular response to gamma radiation Source: UniProtKB
  • positive regulation of neuron apoptotic process Source: UniProtKB
  • positive regulation of oviposition Source: UniProtKB
  • positive regulation of protein processing Source: UniProtKB
  • positive regulation of synapse disassembly Source: UniProtKB
  • programmed cell death Source: WormBase
  • protein autoprocessing Source: UniProtKB
  • protein catabolic process Source: WormBase
  • regulation of cell adhesion Source: UniProtKB
  • regulation of synapse organization Source: UniProtKB

Keywordsi

Molecular functionHydrolase, Protease, Thiol protease
Biological processApoptosis

Enzyme and pathway databases

ReactomeiR-CEL-198323. AKT phosphorylates targets in the cytosol.
R-CEL-448706. Interleukin-1 processing.

Protein family/group databases

MEROPSiC14.002.

Names & Taxonomyi

Protein namesi
Recommended name:
Cell death protein 3 (EC:3.4.22.607 Publications)
Alternative name(s):
Caspase ced-3Curated
Cleaved into the following 3 chains:
Cell death protein 3 subunit p171 Publication
Cell death protein 3 subunit p151 Publication
Cell death protein 3 subunit p131 Publication
Gene namesi
Name:ced-3Imported
ORF Names:C48D1.2Imported
OrganismiCaenorhabditis elegans
Taxonomic identifieri6239 [NCBI]
Taxonomic lineageiEukaryotaMetazoaEcdysozoaNematodaChromadoreaRhabditidaRhabditoideaRhabditidaePeloderinaeCaenorhabditis
Proteomesi
  • UP000001940 Componenti: Chromosome IV

Organism-specific databases

WormBaseiC48D1.2a; CE29088; WBGene00000417; ced-3.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell junction, Cytoplasm, Membrane, Mitochondrion, Nucleus, Synapse

Pathology & Biotechi

Disruption phenotypei

RNAi-mediated knockdown causes a rupture of the vulva and an increase in laid oocytes in a small proportion of animals. In an ain-1 mutant background, enhances the proportion of animals arrested at the larval stage, with egg-laying defects and with a ruptured vulva.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi27L → F in n1040; increased autoprocessing in absence of ced-4. Autoprocessing is blocked in presence of npp-14 and reduced in presence of both ced-4 and npp-14. Loss of embryonic and postembryonic apoptosis resulting in survival of cells in the head, ventral cord, postdeirid sensilla and Q descendants in a ced-1 mutant background defective in cell-corpse clearance. Apoptosis is partially restored in a ced-1 (e1735) and npp-14 (sm160) double mutant background. 2 Publications1
Mutagenesisi30L → F in n2439; increased autoprocessing in absence of ced-4. Autoprocessing is blocked in presence of npp-14 and reduced in presence of both ced-4 and npp-14. Loss of embryonic and postembryonic apoptosis resulting in survival of cells in the anterior pharynx in a ced-1 mutant background defective in cell-corpse clearance. Apoptosis is partially restored in a ced-1 (e1735) and npp-14 (sm160) double mutant background. 1 Publication1
Mutagenesisi51R → H in n2449; normal autoprocessing. No effect on embryonic and postembryonic apoptosis in a ced-1 mutant background defective in cell-corpse clearance. 1 Publication1
Mutagenesisi65G → R in n718; increased autoprocessing in absence of ced-4. Autoprocessing is blocked in presence of npp-14 and reduced in presence of both ced-4 and npp-14. Loss of embryonic and postembryonic apoptosis resulting in survival of cells in the head, ventral cord, postdeirid sensilla and Q descendants in a ced-1 mutant background defective in cell-corpse clearance. Apoptosis is partially restored in a ced-1 (e1735) and npp-14 (sm160) double mutant background. 2 Publications1
Mutagenesisi358C → S: Loss of catalytic activity. Loss of processing. No effect on the interaction with ced-4. Loss of interaction with octameric ced-4; when associated with 391-D--D-393. 3 Publications1
Mutagenesisi360G → S in n2433; loss of catalytic activity. Loss of processing. Severe reduction in the number of apoptotic cells in the anterior pharynx. Loss of embryonic apoptosis in a ced-1 mutant background defective in cell-corpse clearance. Impaired axonal regeneration following injury. Resistance to S.typhimurium-mediated killing. 4 Publications1
Mutagenesisi366G → R in ju1056; Loss of gsnl-1 cleavage. Impaired elimination of presynaptic components in RME neurons in adults. Abnormal accumulation of F-actin at the non-eliminated transient synapses in DD neuron dorsal cord in L4 larvae. 1 Publication1
Mutagenesisi391 – 393LFN → DDD: Loss of interaction with octameric ced-4; when associated with S-358. 1 Publication3
Mutagenesisi449A → V in n1229/n1164; severe reduction in catalytic activity. Partially processed. Reduction in the number of apoptotic cells in the anterior pharynx. In a ced-1 mutant background, loss of embryonic and postembryonic apoptosis resulting in survival of cells in the head, ventral cord, postdeirid sensilla, Q descendants and cells of the anterior pharynx. 2 Publications1
Mutagenesisi474G → R in n2427/n2438; slight reduction in catalytic activity. Almost complete processing. Slight reduction in the number of apoptotic cells in the anterior pharynx. Reduction is higher in a drp-1 or fis-2 mutant background. Reduction in number of eggs laid. In a ced-9 (n1653) mutant background, causes 60 percent embryonic lethality. 3 Publications1

Chemistry databases

ChEMBLiCHEMBL1250361.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
PropeptideiPRO_00004411171 – 2211 PublicationAdd BLAST221
ChainiPRO_0000004674222 – 374Cell death protein 3 subunit p17CuratedAdd BLAST153
ChainiPRO_0000004675375 – 503Cell death protein 3 subunit p15CuratedAdd BLAST129
ChainiPRO_0000441118389 – 503Cell death protein 3 subunit p13CuratedAdd BLAST115

Post-translational modificationi

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).6 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei221 – 222Cleavage; by autolysis1 Publication2
Sitei374 – 375Cleavage; by autolysis1 Publication2
Sitei388 – 389Cleavage; by autolysis1 Publication2

Keywords - PTMi

Autocatalytic cleavage, Zymogen

Proteomic databases

EPDiP42573.
PaxDbiP42573.
PeptideAtlasiP42573.

Expressioni

Developmental stagei

Highly expressed in embryos and to a lesser extent in adults (PubMed:8242740). Expression is low throughout the larval stage (PubMed:8242740). Expressed in all cells, except intestinal cells and their precursors, starting at around 100-150 minutes post-fertilization and continuing throughout the comma stage of embryogenesis (PubMed:17329362). Not expressed after the 3-fold embryonic stage, and only expressed in 2-3 cells in larvae and adults (PubMed:17329362). In males, expressed in the tail at the L4 larval stage (PubMed:17329362). Expression in the tail-spike cell is restricted to the 3-fold embryonic stage prior to the tail-spike cell death (PubMed:17329362).2 Publications

Gene expression databases

BgeeiWBGene00000417.
ExpressionAtlasiP42573. baseline.

Interactioni

Subunit structurei

The active form is probably a heterodimer of the p17 subunit with either the p15 or p13 subunit which are all derived from the precursor by autocatalysis (Probable). Interacts with octameric ced-4 (two ced-3 zymogens per one ced-4 octamer); the interaction causes the autoproteolytic cleavage and activation of ced-3 (PubMed:24065769, PubMed:20434985). Processed ced-3 also interacts with ced-4 octamer to form a stable holoenzyme (PubMed:20434985). Interacts (via large subunit p17) with csp-3; the interaction prevents ced-3 autoactivation and delays ced-4-induced ced-3 processing (PubMed:18776901). Interacts (via large subunit p17 or small subunit p13 or p15) with csp-2; the interaction inhibits ced-3 autoactivation (PubMed:19575016). Interacts (via propeptide) with nucleoporin npp-14; the interaction tethers ced-3 to the nuclear membrane and prevents its autoprocessing in absence of ced-4 (PubMed:27723735). Interacts with dct-1 (PubMed:11114722). May form a complex composed of ced-3, ced-4 and mac-1 (PubMed:10101135).7 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct

Protein-protein interaction databases

BioGridi43363. 5 interactors.
DIPiDIP-244N.
IntActiP42573. 5 interactors.
MINTiMINT-128934.
STRINGi6239.C48D1.2a.

Structurei

Secondary structure

1503
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi214 – 216Combined sources3
Helixi222 – 228Combined sources7
Turni231 – 233Combined sources3
Beta strandi243 – 249Combined sources7
Beta strandi254 – 256Combined sources3
Helixi262 – 275Combined sources14
Beta strandi278 – 285Combined sources8
Helixi288 – 298Combined sources11
Beta strandi306 – 317Combined sources12
Beta strandi320 – 322Combined sources3
Helixi331 – 336Combined sources6
Turni340 – 342Combined sources3
Beta strandi351 – 357Combined sources7
Beta strandi360 – 362Combined sources3
Turni411 – 414Combined sources4
Beta strandi415 – 421Combined sources7
Turni431 – 433Combined sources3
Helixi436 – 448Combined sources13
Turni449 – 451Combined sources3
Helixi454 – 468Combined sources15
Beta strandi471 – 473Combined sources3
Beta strandi476 – 478Combined sources3
Beta strandi483 – 486Combined sources4
Beta strandi489 – 491Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4M9RX-ray2.66A/B198-503[»]
4M9SX-ray3.21E/F/G/H390-397[»]
4M9XX-ray3.34C/D390-395[»]
4M9YX-ray4.20C/D390-397[»]
4M9ZX-ray3.40E/F/G/H390-397[»]
ProteinModelPortaliP42573.
SMRiP42573.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 91CARDPROSITE-ProRule annotationAdd BLAST91

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni389 – 404Required for interaction with ced-41 PublicationAdd BLAST16

Domaini

The CARD domain is involved in ced-4 binding.1 Publication

Sequence similaritiesi

Belongs to the peptidase C14A family.Curated

Phylogenomic databases

eggNOGiKOG3573. Eukaryota.
ENOG410ZQIE. LUCA.
GeneTreeiENSGT00760000118912.
HOGENOMiHOG000016385.
InParanoidiP42573.
KOiK20106.
OMAiGYTVICK.
OrthoDBiEOG091G05YD.
PhylomeDBiP42573.

Family and domain databases

CDDicd00032. CASc. 1 hit.
InterProiView protein in InterPro
IPR001315. CARD.
IPR029030. Caspase-like_dom_sf.
IPR033139. Caspase_cys_AS.
IPR016129. Caspase_his_AS.
IPR011029. DEATH-like_dom_sf.
IPR002138. Pept_C14_p10.
IPR001309. Pept_C14_p20.
IPR015917. Pept_C14A.
PfamiView protein in Pfam
PF00619. CARD. 1 hit.
PRINTSiPR00376. IL1BCENZYME.
SMARTiView protein in SMART
SM00114. CARD. 1 hit.
SM00115. CASc. 1 hit.
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF52129. SSF52129. 1 hit.
PROSITEiView protein in PROSITE
PS50209. CARD. 1 hit.
PS01122. CASPASE_CYS. 1 hit.
PS01121. CASPASE_HIS. 1 hit.
PS50207. CASPASE_P10. 1 hit.
PS50208. CASPASE_P20. 1 hit.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P42573-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MMRQDRRSLL ERNIMMFSSH LKVDEILEVL IAKQVLNSDN GDMINSCGTV
60 70 80 90 100
REKRREIVKA VQRRGDVAFD AFYDALRSTG HEGLAEVLEP LARSVDSNAV
110 120 130 140 150
EFECPMSPAS HRRSRALSPA GYTSPTRVHR DSVSSVSSFT SYQDIYSRAR
160 170 180 190 200
SRSRSRALHS SDRHNYSSPP VNAFPSQPSS ANSSFTGCSS LGYSSSRNRS
210 220 230 240 250
FSKASGPTQY IFHEEDMNFV DAPTISRVFD EKTMYRNFSS PRGMCLIINN
260 270 280 290 300
EHFEQMPTRN GTKADKDNLT NLFRCMGYTV ICKDNLTGRG MLLTIRDFAK
310 320 330 340 350
HESHGDSAIL VILSHGEENV IIGVDDIPIS THEIYDLLNA ANAPRLANKP
360 370 380 390 400
KIVFVQACRG ERRDNGFPVL DSVDGVPAFL RRGWDNRDGP LFNFLGCVRP
410 420 430 440 450
QVQQVWRKKP SQADILIAYA TTAQYVSWRN SARGSWFIQA VCEVFSTHAK
460 470 480 490 500
DMDVVELLTE VNKKVACGFQ TSQGSNILKQ MPEMTSRLLK KFYFWPEARN

SAV
Length:503
Mass (Da):56,617
Last modified:August 14, 2001 - v2
Checksum:i722D5831F94DAA69
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L29052 Genomic DNA. Translation: AAA27982.2.
AF210702 mRNA. Translation: AAG42045.1.
Z81049 Genomic DNA. Translation: CAB61001.2.
PIRiA49429.
RefSeqiNP_001255708.1. NM_001268779.1.
UniGeneiCel.19438.

Genome annotation databases

EnsemblMetazoaiC48D1.2a; C48D1.2a; WBGene00000417.
GeneIDi178272.
KEGGicel:CELE_C48D1.2.
UCSCiC48D1.2. c. elegans.

Similar proteinsi

Entry informationi

Entry nameiCED3_CAEEL
AccessioniPrimary (citable) accession number: P42573
Secondary accession number(s): P45435, Q9GQQ4, Q9NAQ8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: August 14, 2001
Last modified: November 22, 2017
This is version 149 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programCaenorhabditis annotation project

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Caenorhabditis elegans
    Caenorhabditis elegans: entries, gene names and cross-references to WormBase
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. Peptidase families
    Classification of peptidase families and list of entries
  4. SIMILARITY comments
    Index of protein domains and families