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Protein

Receptor-interacting serine/threonine-protein kinase 3

Gene

RIPK3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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.7 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-containing complex binding Source: UniProtKB
  • protein kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB
  • transcription coactivator activity Source: ProtInc

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processNecrosis
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-168927 TICAM1, RIP1-mediated IKK complex recruitment
R-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-9013957 TLR3-mediated TICAM1-dependent programmed cell death
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

EuPathDBiHostDB:ENSG00000129465.15
HGNCiHGNC:10021 RIPK3
MIMi605817 gene
neXtProtiNX_Q9Y572

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 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. Loss of interaction with PELI1 and PELI1-mediated ubiquitination. No loss of STUB1-mediated ubiquitination. 4 Publications1
Mutagenesisi50K → D: Abolishes kinase activity. 3 Publications1
Mutagenesisi142D → N: Abolishes kinase activity and ability to mediate necroptosis. 1 Publication1
Mutagenesisi182T → A: Abolishes kinase activity. Loss of interaction with PELI1 and PELI1-mediated ubiquitination. No loss of interaction with STUB1 and STUB1-mediated ubiquitination. No loss of interaction with RIPK1. Loss of ability to mediate TNF-induced necroptosis. Loss of autophosphorylation at Ser-227. 1 Publication1
Mutagenesisi182T → S: No loss of interaction with PELI1 and PELI1-mediated ubiquitination. No loss of interaction with RIPK1 and MLKL. 1 Publication1
Mutagenesisi185Y → A or F: Loss of interaction with PELI1 and PELI1-mediated ubiquitination. 1 Publication1
Mutagenesisi227S → A: Abolishes ability to mediate necroptosis. Partial loss of kinase activity. No loss of PELI1-mediated degradation. 2 Publications1
Mutagenesisi227S → D: No loss of PELI1-mediated degradation. 1 Publication1
Mutagenesisi363K → R: Loss of PELI1-mediated ubiquitination. No loss of interaction with PELI1. 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 residuei182Phosphothreonine1 Publication1
Modified residuei199Phosphoserine; by autocatalysis2 Publications1
Modified residuei227Phosphoserine; by autocatalysis2 Publications1
Modified residuei252PhosphothreonineBy similarity1
Modified residuei299PhosphoserineBy similarity1
Modified residuei333PhosphothreonineBy similarity1
Cross-linki363Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
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 (PubMed:11734559, PubMed:19524512, PubMed:22265413). Phosphorylation at Thr-182 is important for its kinase activity, interaction with PELI1 and PELI1-mediated 'Lys-48'-linked polyubiquitination and for its ability to mediate TNF-induced necroptosis (PubMed:29883609).4 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 (PubMed:21931591). Polyubiquitinated with 'Lys-48'-linked chains by PELI1 leading to its subsequent proteasome-dependent degradation. Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent degradation (PubMed:29883609).2 Publications

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ9Y572
PeptideAtlasiQ9Y572
PRIDEiQ9Y572
ProteomicsDBi86299
86300 [Q9Y572-2]
86301 [Q9Y572-3]

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 Expressed in 128 organ(s), highest expression level in blood
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. Interacts with PELI1 (via atypical FHA domain); the phosphorylated form at Thr-182 binds preferentially to PELI1 (PubMed:29883609). Interacts with BUB1B, TRAF2 and STUB1 (PubMed:29883609). Interacts with ZBP1 (By similarity).By similarity10 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi116224, 26 interactors
DIPiDIP-27519N
IntActiQ9Y572, 13 interactors
MINTiQ9Y572
STRINGi9606.ENSP00000216274

Chemistry databases

BindingDBiQ9Y572

Structurei

Secondary structure

1518
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

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

Phylogenomic databases

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

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR025735 RHIM_dom
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
PF12721 RHIM, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

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

This entry has 3 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H0YJN5H0YJN5_HUMAN
Receptor-interacting serine/threoni...
RIPK3
162Annotation score:

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 dbSNP:rs7153640Ensembl.1
Natural variantiVAR_041048300T → M1 PublicationCorresponds to variant dbSNP:rs34106261Ensembl.1
Natural variantiVAR_041049492P → Q1 PublicationCorresponds to variant dbSNP:rs3212254Ensembl.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]
ENST00000643393; ENSP00000495915; ENSG00000285379 [Q9Y572-3]
ENST00000646516; ENSP00000495490; ENSG00000285379 [Q9Y572-1]
GeneIDi11035
KEGGihsa:11035
UCSCiuc001wpb.4 human [Q9Y572-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

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

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5V7ZNMR-A/C/E/G448-462[»]
ProteinModelPortaliQ9Y572
SMRiQ9Y572
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116224, 26 interactors
DIPiDIP-27519N
IntActiQ9Y572, 13 interactors
MINTiQ9Y572
STRINGi9606.ENSP00000216274

Chemistry databases

BindingDBiQ9Y572
ChEMBLiCHEMBL1795199

PTM databases

iPTMnetiQ9Y572
PhosphoSitePlusiQ9Y572

Polymorphism and mutation databases

BioMutaiRIPK3
DMDMi205371831

Proteomic databases

PaxDbiQ9Y572
PeptideAtlasiQ9Y572
PRIDEiQ9Y572
ProteomicsDBi86299
86300 [Q9Y572-2]
86301 [Q9Y572-3]

Protocols and materials databases

DNASUi11035
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000216274; ENSP00000216274; ENSG00000129465 [Q9Y572-1]
ENST00000554756; ENSP00000452328; ENSG00000129465 [Q9Y572-3]
ENST00000643393; ENSP00000495915; ENSG00000285379 [Q9Y572-3]
ENST00000646516; ENSP00000495490; ENSG00000285379 [Q9Y572-1]
GeneIDi11035
KEGGihsa:11035
UCSCiuc001wpb.4 human [Q9Y572-1]

Organism-specific databases

CTDi11035
DisGeNETi11035
EuPathDBiHostDB:ENSG00000129465.15
GeneCardsiRIPK3
HGNCiHGNC:10021 RIPK3
HPAiHPA055087
MIMi605817 gene
neXtProtiNX_Q9Y572
OpenTargetsiENSG00000129465
PharmGKBiPA34396
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-168927 TICAM1, RIP1-mediated IKK complex recruitment
R-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-9013957 TLR3-mediated TICAM1-dependent programmed cell death
R-HSA-937041 IKK complex recruitment mediated by RIP1
SignaLinkiQ9Y572
SIGNORiQ9Y572

Miscellaneous databases

GeneWikiiRIPK3
GenomeRNAii11035
PROiPR:Q9Y572
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000129465 Expressed in 128 organ(s), highest expression level in blood
CleanExiHS_RIPK3
ExpressionAtlasiQ9Y572 baseline and differential
GenevisibleiQ9Y572 HS

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR025735 RHIM_dom
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
PF12721 RHIM, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiRIPK3_HUMAN
AccessioniPrimary (citable) accession number: Q9Y572
Secondary accession number(s): B4DJL9
, C4AM87, Q5J795, Q5J796, Q6P5Y1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: September 2, 2008
Last modified: November 7, 2018
This is version 181 of the entry and version 2 of the sequence. See 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

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
  7. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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