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Protein

Cell death protein 4

Gene

ced-4

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

Functioni

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). During oogenesis, required for germline apoptosis downstream of ced-9 and upstream of ced-3 but independently of egl-1 (PubMed:9927601). May regulate germline apoptosis in response to DNA damage, probably downstream of let-60/ras and mpk-1 pathway (PubMed:21901106). Regulates CEP neuron apoptosis in response to high Al3+ levels (PubMed:23106139). During male tail morphogenesis, promotes apoptosis of the tail-spike cell upstream of ced-3 but independently of egl-1 and ced-9 (PubMed:17329362). May play a role in sex-specific cell apoptosis, probably by promoting ced-3-mediated cleavage of sex-determining protein fem-1 (PubMed:10764728). During larval development, required for the elimination of transient presynaptic components downstream of egl-1 and ced-9 and upstream of ced-3 apoptotic pathway (PubMed:26074078). Downstream of calreticulin crt-1 and upstream of ced-3 and independently of egl-1 and ced-9, plays a role in the initial steps of axonal regrowth following axotomy (PubMed:22629231). Together with ain-1, a component of the miRNA-induced-silencing complex (miRISC), and probably upstream of ced-3, regulates temporal cell fate patterning during larval development (PubMed:25432023). May play a role in resistance to S.typhimurium-mediated infection (PubMed:11226309).10 Publications
Isoform a: Plays a major role in programmed cell death (PubMed:1286611, PubMed:8706125). egl-1 binds to and directly inhibits the activity of ced-9, releasing the cell death activator ced-4 from a ced-9/ced-4 containing protein complex and allowing ced-4 to induce caspase ced-3 autoproteolytic cleavage and activation (PubMed:15383288, PubMed:16208361, PubMed:20434985, PubMed:24065769). Also forms an holoenzyme with processed ced-3 enhancing ced-3 activity (PubMed:20434985).7 Publications
Isoform b: Prevents programmed cell death.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei131ATP; via carbonyl oxygenCombined sources3 Publications1
Metal bindingi166Magnesium2 Publications1
Binding sitei171ATPCombined sources1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi162 – 167ATPCombined sources3 Publications6

GO - Molecular functioni

  • ADP binding Source: InterPro
  • ATP binding Source: WormBase
  • BH1 domain binding Source: WormBase
  • BH3 domain binding Source: WormBase
  • caspase binding Source: UniProtKB
  • cysteine-type endopeptidase activator activity involved in apoptotic process Source: UniProtKB
  • endopeptidase activator activity Source: WormBase
  • metal ion binding Source: UniProtKB-KW
  • peptidase activator activity involved in apoptotic process Source: WormBase

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
  • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c Source: GO_Central
  • apoptotic process Source: UniProtKB
  • apoptotic process involved in development Source: UniProtKB
  • embryo development ending in birth or egg hatching Source: WormBase
  • embryonic morphogenesis Source: WormBase
  • negative regulation of apoptotic process Source: UniProtKB
  • positive regulation of apoptotic process Source: WormBase
  • positive regulation of apoptotic process involved in development Source: UniProtKB
  • positive regulation of cysteine-type endopeptidase activity Source: WormBase
  • positive regulation of protein processing Source: UniProtKB
  • positive regulation of synapse disassembly Source: UniProtKB
  • protein homotetramerization Source: UniProtKB
  • regulation of cell adhesion Source: UniProtKB
  • regulation of cell size Source: WormBase
  • regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: WormBase

Keywordsi

Biological processApoptosis
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Cell death protein 4
Gene namesi
Name:ced-4
ORF Names:C35D10.9
OrganismiCaenorhabditis elegans
Taxonomic identifieri6239 [NCBI]
Taxonomic lineageiEukaryotaMetazoaEcdysozoaNematodaChromadoreaRhabditidaRhabditoideaRhabditidaePeloderinaeCaenorhabditis
Proteomesi
  • UP000001940 Componenti: Chromosome III

Organism-specific databases

WormBaseiC35D10.9a; CE01203; WBGene00000418; ced-4.
C35D10.9b; CE38154; WBGene00000418; ced-4.

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

Cytoplasm, Mitochondrion

Pathology & Biotechi

Disruption phenotypei

Mutants exhibit a block in almost all programmed cell deaths that normally occur during development (PubMed:1286611). RNAi-mediated knockdown causes a defect in egg laying in a small proportion of animals (PubMed:25432023). Also causes a moderate increase in CEP neuron survival in response to high Al3+ levels (PubMed:23106139). 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 (PubMed:25432023).3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi252V → D: Loss of dimerization without affecting interaction with ced-9, loss of ced-3 activation and severe reduction in the number of cell corpses in embryos in a ced-1 mutant background; when associated with E-255 and E-256. 1 Publication1
Mutagenesisi255R → E: Severe reduction in the number of cell corpses in embryos in a ced-1 mutant background. Loss of dimerization without affecting interaction with ced-9, loss of ced-3 activation and severe reduction in the number of cell corpses in embryos in a ced-1 mutant background; when associated with E-252 and E-256. 1 Publication1
Mutagenesisi256M → E: Loss of dimerization without affecting interaction with ced-9, loss of ced-3 activation and severe reduction in the number of cell corpses in embryos in a ced-1 mutant background; when associated with E-252 and E-255. 1 Publication1
Mutagenesisi272 – 273DD → AA: Severe reduction in the number of cell corpses in embryos in a ced-1 mutant background. 1 Publication2
Mutagenesisi280I → N in n1948; no effect on the interaction with mac-1. 1 Publication1
Mutagenesisi416A → W: Reduced interaction with ced-3. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000894701 – 571Cell death protein 4Add BLAST571

Proteomic databases

EPDiP30429.
PaxDbiP30429.
PeptideAtlasiP30429.
PRIDEiP30429.

Expressioni

Developmental stagei

Abundantly expressed during embryogenesis and to a lesser extent in larvae and adults (PubMed:1286611). Expression starts at the 100-cell stage and persists through embryogenesis (at protein level) (PubMed:9027313). Not expressed in larvae and adults (at protein level) (PubMed:9027313).2 Publications

Gene expression databases

BgeeiWBGene00000418.

Interactioni

Subunit structurei

Associates as an asymmetric homodimer with ced-9 (PubMed:16208361, PubMed:9027313, PubMed:15383288). Upon release from ced-9, forms an octamer, known as the apoptosome, and interacts with ced-3; the interaction results in ced-3 autoproteolytic cleavage and activation (PubMed:20434985, PubMed:24065769). The octamer (a tetramer of an asymmetric dimer) also interacts with two processed ced-3 to form a stable holoenzyme (PubMed:20434985). Interacts with sex-determining protein fem-1 (PubMed:10764728). May form a complex composed of ced-3, ced-4 and mac-1 or of ced-9, ced-4 and mac-1 (PubMed:10101135). Within the complex, interacts with ced-4 (PubMed:10101135).7 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • BH1 domain binding Source: WormBase
  • BH3 domain binding Source: WormBase
  • caspase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi40877. 5 interactors.
DIPiDIP-1016N.
IntActiP30429. 6 interactors.
MINTiMINT-128892.
STRINGi6239.C35D10.9b.

Structurei

Secondary structure

1571
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi4 – 20Combined sources17
Helixi23 – 26Combined sources4
Helixi27 – 32Combined sources6
Helixi38 – 45Combined sources8
Beta strandi47 – 49Combined sources3
Helixi50 – 64Combined sources15
Beta strandi66 – 68Combined sources3
Helixi69 – 77Combined sources9
Helixi81 – 96Combined sources16
Helixi101 – 104Combined sources4
Turni105 – 108Combined sources4
Helixi112 – 121Combined sources10
Helixi134 – 147Combined sources14
Beta strandi150 – 158Combined sources9
Helixi165 – 175Combined sources11
Turni181 – 183Combined sources3
Beta strandi184 – 191Combined sources8
Beta strandi196 – 198Combined sources3
Helixi199 – 211Combined sources13
Beta strandi239 – 241Combined sources3
Helixi250 – 261Combined sources12
Beta strandi267 – 274Combined sources8
Helixi277 – 285Combined sources9
Beta strandi289 – 296Combined sources8
Helixi297 – 302Combined sources6
Beta strandi307 – 311Combined sources5
Helixi317 – 326Combined sources10
Helixi336 – 348Combined sources13
Helixi352 – 359Combined sources8
Beta strandi364 – 366Combined sources3
Helixi367 – 380Combined sources14
Helixi381 – 384Combined sources4
Beta strandi389 – 395Combined sources7
Helixi396 – 405Combined sources10
Helixi409 – 414Combined sources6
Helixi417 – 419Combined sources3
Helixi429 – 435Combined sources7
Helixi450 – 458Combined sources9
Turni459 – 461Combined sources3
Beta strandi462 – 464Combined sources3
Beta strandi466 – 469Combined sources4
Beta strandi471 – 473Combined sources3
Beta strandi475 – 477Combined sources3
Helixi480 – 487Combined sources8
Helixi493 – 499Combined sources7
Turni503 – 505Combined sources3
Turni510 – 512Combined sources3
Helixi555 – 558Combined sources4
Helixi559 – 562Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2A5YX-ray2.60B/C1-571[»]
3LQQX-ray3.53A/B1-571[»]
3LQRX-ray3.90A/B1-571[»]
4M9SX-ray3.21A/B/C/D1-571[»]
4M9XX-ray3.34A/B1-571[»]
4M9YX-ray4.20A/B1-571[»]
4M9ZX-ray3.40A/B/C/D1-571[»]
ProteinModelPortaliP30429.
SMRiP30429.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP30429.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 91CARDPROSITE-ProRule annotationAdd BLAST91
Domaini133 – 439NB-ARCSequence analysisAdd BLAST307

Phylogenomic databases

eggNOGiKOG4658. Eukaryota.
COG4886. LUCA.
HOGENOMiHOG000111533.
InParanoidiP30429.
KOiK20105.
OMAiAIMESYK.
OrthoDBiEOG091G05PL.
PhylomeDBiP30429.

Family and domain databases

InterProiView protein in InterPro
IPR016854. Apop_reg_Ced-4.
IPR001315. CARD.
IPR011029. DEATH-like_dom_sf.
IPR002182. NB-ARC.
IPR027417. P-loop_NTPase.
IPR036390. WH_DNA-bd_sf.
PfamiView protein in Pfam
PF00619. CARD. 1 hit.
PF00931. NB-ARC. 1 hit.
PIRSFiPIRSF027202. Apop_reg_Ced-4. 1 hit.
SMARTiView protein in SMART
SM00114. CARD. 1 hit.
SUPFAMiSSF46785. SSF46785. 1 hit.
SSF47986. SSF47986. 1 hit.
SSF52540. SSF52540. 1 hit.
PROSITEiView protein in PROSITE
PS50209. CARD. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform b (identifier: P30429-1) [UniParc]FASTAAdd to basket
Also known as: Long

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MLCEIECRAL STAHTRLIHD FEPRDALTYL EGKNIFTEDH SELISKMSTR
60 70 80 90 100
LERIANFLRI YRRQASELGP LIDFFNYNNQ SHLADFLEDY IDFAINEPDL
110 120 130 140 150
LRPVVIAPQF SRQMLDRKLL LGNVPKQMTC YIREYHVDRV IKKLDEMCDL
160 170 180 190 200
DSFFLFLHGR AGSGKSVIAS QALSKSDQLI GINYDSIVWL KDSGTAPKST
210 220 230 240 250
FDLFTDILLM LARVVSDTDD SHSITDFINR VLSRSEDDLL NFPSVEHVTS
260 270 280 290 300
VVLKRMICNA LIDRPNTLFV FDDVVQEETI RWAQELRLRC LVTTRDVEIS
310 320 330 340 350
NAASQTCEFI EVTSLEIDEC YDFLEAYGMP MPVGEKEEDV LNKTIELSSG
360 370 380 390 400
NPATLMMFFK SCEPKTFEKM AQLNNKLESR GLVGVECITP YSYKSLAMAL
410 420 430 440 450
QRCVEVLSDE DRSALAFAVV MPPGVDIPVK LWSCVIPVDI CSNEEEQLDD
460 470 480 490 500
EVADRLKRLS KRGALLSGKR MPVLTFKIDH IIHMFLKHVV DAQTIANGIS
510 520 530 540 550
ILEQRLLEIG NNNVSVPERH IPSHFQKFRR SSASEMYPKT TEETVIRPED
560 570
FPKFMQLHQK FYDSLKNFAC C
Note: Minor transcript.
Length:571
Mass (Da):65,336
Last modified:March 29, 2005 - v2
Checksum:i6BE9893946B79E6C
GO
Isoform a (identifier: P30429-2) [UniParc]FASTAAdd to basket
Also known as: Short

The sequence of this isoform differs from the canonical sequence as follows:
     212-234: ARVVSDTDDSHSITDFINRVLSR → K

Note: Major transcript.
Show »
Length:549
Mass (Da):62,878
Checksum:iDB2A7969BDA50AF8
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_013199212 – 234ARVVS…RVLSR → K in isoform a. CuratedAdd BLAST23

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X69016 Genomic DNA. Translation: CAA48781.1.
FO080789 Genomic DNA. Translation: CCD66781.1.
FO080789 Genomic DNA. Translation: CCD66782.1.
PIRiS72566.
RefSeqiNP_001021202.1. NM_001026031.2. [P30429-2]
NP_001021203.1. NM_001026032.1. [P30429-1]
UniGeneiCel.10679.

Genome annotation databases

EnsemblMetazoaiC35D10.9b; C35D10.9b; WBGene00000418. [P30429-1]
GeneIDi175643.
KEGGicel:CELE_C35D10.9.
UCSCiC35D10.9b. c. elegans. [P30429-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiCED4_CAEEL
AccessioniPrimary (citable) accession number: P30429
Secondary accession number(s): Q5BHI5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: March 29, 2005
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, 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