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Protein

Receptor-interacting serine/threonine-protein kinase 3

Gene

RIPK3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Essential for necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 and MLKL to form a necrosis-inducing complex. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production.6 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei50ATP1
Active sitei142Proton acceptor1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi27 – 35ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • identical protein binding Source: IntAct
  • NF-kappaB-inducing kinase activity Source: Ensembl
  • protein complex binding Source: UniProtKB
  • protein kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB
  • transcription coactivator activity Source: ProtInc

GO - Biological processi

  • activation of protein kinase activity Source: UniProtKB
  • amyloid fibril formation Source: UniProtKB
  • apoptotic signaling pathway Source: ProtInc
  • cellular protein modification process Source: ProtInc
  • I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  • lymph node development Source: UniProtKB
  • necroptotic process Source: UniProtKB
  • positive regulation of intrinsic apoptotic signaling pathway Source: Ensembl
  • positive regulation of ligase activity Source: Ensembl
  • positive regulation of necroptotic process Source: UniProtKB
  • positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • positive regulation of oxidoreductase activity Source: Ensembl
  • positive regulation of phosphatase activity Source: UniProtKB
  • positive regulation of protein deacetylation Source: Ensembl
  • positive regulation of reactive oxygen species metabolic process Source: Ensembl
  • protein autophosphorylation Source: UniProtKB
  • protein heterooligomerization Source: UniProtKB
  • protein homooligomerization Source: UniProtKB
  • regulation of activated T cell proliferation Source: UniProtKB
  • regulation of activation-induced cell death of T cells Source: UniProtKB
  • regulation of adaptive immune response Source: UniProtKB
  • regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation Source: UniProtKB
  • regulation of interferon-gamma production Source: UniProtKB
  • regulation of T cell mediated cytotoxicity Source: UniProtKB
  • signal transduction Source: ProtInc
  • spleen development Source: UniProtKB
  • T cell differentiation in thymus Source: UniProtKB
  • T cell homeostasis Source: UniProtKB
  • thymus development Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Necrosis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS05280-MONOMER.
BRENDAi2.7.10.2. 2681.
ReactomeiR-HSA-1810476. RIP-mediated NFkB activation via ZBP1.
R-HSA-2562578. TRIF-mediated programmed cell death.
R-HSA-3295583. TRP channels.
R-HSA-5213460. RIPK1-mediated regulated necrosis.
R-HSA-937041. IKK complex recruitment mediated by RIP1.
SignaLinkiQ9Y572.
SIGNORiQ9Y572.

Names & Taxonomyi

Protein namesi
Recommended name:
Receptor-interacting serine/threonine-protein kinase 3 (EC:2.7.11.1)
Alternative name(s):
RIP-like protein kinase 3
Receptor-interacting protein 3
Short name:
RIP-3
Gene namesi
Name:RIPK3
Synonyms:RIP3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:10021. RIPK3.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: UniProtKB
  • mitochondrion Source: UniProtKB-SubCell
  • plasma membrane Source: UniProtKB-SubCell
  • ripoptosome Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Mitochondrion

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi50K → A: Abolishes kinase activity. Loss of PGAM5- and MLKL-binding. No effect on RIPK1-binding. 3 Publications1
Mutagenesisi50K → D: Abolishes kinase activity. 3 Publications1
Mutagenesisi142D → N: Abolishes kinase activity and ability to mediate necroptosis. 1 Publication1
Mutagenesisi227S → A: Abolishes ability to mediate necroptosis. 1 Publication1

Organism-specific databases

DisGeNETi11035.
OpenTargetsiENSG00000129465.
PharmGKBiPA34396.

Chemistry databases

ChEMBLiCHEMBL1795199.

Polymorphism and mutation databases

BioMutaiRIPK3.
DMDMi205371831.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000866101 – 518Receptor-interacting serine/threonine-protein kinase 3Add BLAST518

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2PhosphoserineBy similarity1
Modified residuei164PhosphoserineBy similarity1
Modified residuei199Phosphoserine; by autocatalysis2 Publications1
Modified residuei227Phosphoserine1 Publication1
Modified residuei252PhosphothreonineBy similarity1
Modified residuei299PhosphoserineBy similarity1
Modified residuei333PhosphothreonineBy similarity1
Modified residuei389PhosphoserineBy similarity1
Modified residuei401PhosphothreonineBy similarity1

Post-translational modificationi

RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylation of Ser-199 plays a role in the necroptotic function of RIPK3. Phosphorylation at Ser-227 is required for binding MLKL.3 Publications
Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ9Y572.
PeptideAtlasiQ9Y572.
PRIDEiQ9Y572.

PTM databases

iPTMnetiQ9Y572.
PhosphoSitePlusiQ9Y572.

Expressioni

Tissue specificityi

Highly expressed in the pancreas. Detected at lower levels in heart, placenta, lung and kidney. Isoform 3 is significantly increased in colon and lung cancers.1 Publication

Gene expression databases

BgeeiENSG00000129465.
CleanExiHS_RIPK3.
ExpressionAtlasiQ9Y572. baseline and differential.
GenevisibleiQ9Y572. HS.

Organism-specific databases

HPAiHPA055087.

Interactioni

Subunit structurei

Interacts (via RIP homotypic interaction motif) with RIPK1 (via RIP homotypic interaction motif); this interaction induces RIPK1 phosphorylation and formation of a RIPK1-RIPK3 necrosis-inducing complex. Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity. Interacts with MLKL; the interaction is direct. Binds TRAF2 and is recruited to the TNFR-1 signaling complex. Interacts with PYGL, GLUL and GLUD1; these interactions result in activation of these metabolic enzymes. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with ARHGEF2.9 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself5EBI-298250,EBI-298250
BIRC2Q134903EBI-298250,EBI-514538
BIRC3Q134893EBI-298250,EBI-517709
MLKLQ8NB1610EBI-298250,EBI-1055040
RIPK1Q1354626EBI-298250,EBI-358507
SIRT2Q8IXJ62EBI-298250,EBI-477232
ZBP1Q9H1714EBI-298250,EBI-6264672

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • protein complex binding Source: UniProtKB

Protein-protein interaction databases

BioGridi116224. 24 interactors.
DIPiDIP-27519N.
IntActiQ9Y572. 14 interactors.
MINTiMINT-1131399.
STRINGi9606.ENSP00000216274.

Chemistry databases

BindingDBiQ9Y572.

Structurei

3D structure databases

ProteinModelPortaliQ9Y572.
SMRiQ9Y572.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini21 – 287Protein kinasePROSITE-ProRule annotationAdd BLAST267

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi450 – 466RIP homotypic interaction motif (RHIM)Add BLAST17

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi357 – 448Pro-richAdd BLAST92

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00550000074536.
HOGENOMiHOG000035101.
HOVERGENiHBG062538.
InParanoidiQ9Y572.
KOiK08847.
OMAiVTKFMEN.
OrthoDBiEOG091G0DXD.
PhylomeDBiQ9Y572.
TreeFamiTF106506.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR025735. RHIM_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
PF12721. RHIM. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9Y572-1) [UniParc]FASTAAdd to basket

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
MSCVKLWPSG APAPLVSIEE LENQELVGKG GFGTVFRAQH RKWGYDVAVK
60 70 80 90 100
IVNSKAISRE VKAMASLDNE FVLRLEGVIE KVNWDQDPKP ALVTKFMENG
110 120 130 140 150
SLSGLLQSQC PRPWPLLCRL LKEVVLGMFY LHDQNPVLLH RDLKPSNVLL
160 170 180 190 200
DPELHVKLAD FGLSTFQGGS QSGTGSGEPG GTLGYLAPEL FVNVNRKAST
210 220 230 240 250
ASDVYSFGIL MWAVLAGREV ELPTEPSLVY EAVCNRQNRP SLAELPQAGP
260 270 280 290 300
ETPGLEGLKE LMQLCWSSEP KDRPSFQECL PKTDEVFQMV ENNMNAAVST
310 320 330 340 350
VKDFLSQLRS SNRRFSIPES GQGGTEMDGF RRTIENQHSR NDVMVSEWLN
360 370 380 390 400
KLNLEEPPSS VPKKCPSLTK RSRAQEEQVP QAWTAGTSSD SMAQPPQTPE
410 420 430 440 450
TSTFRNQMPS PTSTGTPSPG PRGNQGAERQ GMNWSCRTPE PNPVTGRPLV
460 470 480 490 500
NIYNCSGVQV GDNNYLTMQQ TTALPTWGLA PSGKGRGLQH PPPVGSQEGP
510
KDPEAWSRPQ GWYNHSGK
Length:518
Mass (Da):56,887
Last modified:September 2, 2008 - v2
Checksum:iBF755F8A0B1810A1
GO
Isoform 2 (identifier: Q9Y572-2) [UniParc]FASTAAdd to basket
Also known as: Beta

The sequence of this isoform differs from the canonical sequence as follows:
     220-518: VELPTEPSLV...PQGWYNHSGK → CQPNHHSCTKQCATGRTGLHWLSCPKPGLRLPA

Show »
Length:252
Mass (Da):27,574
Checksum:i20D7DFAB11AEECEF
GO
Isoform 3 (identifier: Q9Y572-3) [UniParc]FASTAAdd to basket
Also known as: Gamma

The sequence of this isoform differs from the canonical sequence as follows:
     222-518: LPTEPSLVYE...PQGWYNHSGK → CKTLGGFWDP

Show »
Length:231
Mass (Da):25,326
Checksum:i8E6E045EC3B11DEF
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti30G → D in AAD39005 (PubMed:10339433).Curated1
Sequence conflicti150L → P in AAD39005 (PubMed:10339433).Curated1
Sequence conflicti309R → K in AAD39005 (PubMed:10339433).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_051664260E → V.Corresponds to variant rs7153640dbSNPEnsembl.1
Natural variantiVAR_041048300T → M.1 PublicationCorresponds to variant rs34106261dbSNPEnsembl.1
Natural variantiVAR_041049492P → Q.1 PublicationCorresponds to variant rs3212254dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_035106220 – 518VELPT…NHSGK → CQPNHHSCTKQCATGRTGLH WLSCPKPGLRLPA in isoform 2. 1 PublicationAdd BLAST299
Alternative sequenceiVSP_035107222 – 518LPTEP…NHSGK → CKTLGGFWDP in isoform 3. 2 PublicationsAdd BLAST297

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF156884 mRNA. Translation: AAD39005.1.
AY453693 mRNA. Translation: AAS16359.1.
AY494982 mRNA. Translation: AAS75516.1.
AY494983 mRNA. Translation: AAS75517.1.
AL096870 Genomic DNA. No translation available.
AK296140 mRNA. Translation: BAG58881.1.
CH471078 Genomic DNA. Translation: EAW66021.1.
BC062584 mRNA. Translation: AAH62584.1.
CCDSiCCDS9628.1. [Q9Y572-1]
RefSeqiNP_006862.2. NM_006871.3. [Q9Y572-1]
UniGeneiHs.268551.

Genome annotation databases

EnsembliENST00000216274; ENSP00000216274; ENSG00000129465. [Q9Y572-1]
ENST00000554756; ENSP00000452328; ENSG00000129465. [Q9Y572-3]
GeneIDi11035.
KEGGihsa:11035.
UCSCiuc001wpb.4. human. [Q9Y572-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF156884 mRNA. Translation: AAD39005.1.
AY453693 mRNA. Translation: AAS16359.1.
AY494982 mRNA. Translation: AAS75516.1.
AY494983 mRNA. Translation: AAS75517.1.
AL096870 Genomic DNA. No translation available.
AK296140 mRNA. Translation: BAG58881.1.
CH471078 Genomic DNA. Translation: EAW66021.1.
BC062584 mRNA. Translation: AAH62584.1.
CCDSiCCDS9628.1. [Q9Y572-1]
RefSeqiNP_006862.2. NM_006871.3. [Q9Y572-1]
UniGeneiHs.268551.

3D structure databases

ProteinModelPortaliQ9Y572.
SMRiQ9Y572.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116224. 24 interactors.
DIPiDIP-27519N.
IntActiQ9Y572. 14 interactors.
MINTiMINT-1131399.
STRINGi9606.ENSP00000216274.

Chemistry databases

BindingDBiQ9Y572.
ChEMBLiCHEMBL1795199.

PTM databases

iPTMnetiQ9Y572.
PhosphoSitePlusiQ9Y572.

Polymorphism and mutation databases

BioMutaiRIPK3.
DMDMi205371831.

Proteomic databases

PaxDbiQ9Y572.
PeptideAtlasiQ9Y572.
PRIDEiQ9Y572.

Protocols and materials databases

DNASUi11035.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000216274; ENSP00000216274; ENSG00000129465. [Q9Y572-1]
ENST00000554756; ENSP00000452328; ENSG00000129465. [Q9Y572-3]
GeneIDi11035.
KEGGihsa:11035.
UCSCiuc001wpb.4. human. [Q9Y572-1]

Organism-specific databases

CTDi11035.
DisGeNETi11035.
GeneCardsiRIPK3.
HGNCiHGNC:10021. RIPK3.
HPAiHPA055087.
MIMi605817. gene.
neXtProtiNX_Q9Y572.
OpenTargetsiENSG00000129465.
PharmGKBiPA34396.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00550000074536.
HOGENOMiHOG000035101.
HOVERGENiHBG062538.
InParanoidiQ9Y572.
KOiK08847.
OMAiVTKFMEN.
OrthoDBiEOG091G0DXD.
PhylomeDBiQ9Y572.
TreeFamiTF106506.

Enzyme and pathway databases

BioCyciZFISH:HS05280-MONOMER.
BRENDAi2.7.10.2. 2681.
ReactomeiR-HSA-1810476. RIP-mediated NFkB activation via ZBP1.
R-HSA-2562578. TRIF-mediated programmed cell death.
R-HSA-3295583. TRP channels.
R-HSA-5213460. RIPK1-mediated regulated necrosis.
R-HSA-937041. IKK complex recruitment mediated by RIP1.
SignaLinkiQ9Y572.
SIGNORiQ9Y572.

Miscellaneous databases

GeneWikiiRIPK3.
GenomeRNAii11035.
PROiQ9Y572.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000129465.
CleanExiHS_RIPK3.
ExpressionAtlasiQ9Y572. baseline and differential.
GenevisibleiQ9Y572. HS.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR025735. RHIM_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
PF12721. RHIM. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiRIPK3_HUMAN
AccessioniPrimary (citable) accession number: Q9Y572
Secondary accession number(s): B4DJL9
, C4AM87, Q5J795, Q5J796, Q6P5Y1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: September 2, 2008
Last modified: November 30, 2016
This is version 164 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.