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Protein

Receptor-interacting serine/threonine-protein kinase 3

Gene

Ripk3

Organism
Mus musculus (Mouse)
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.4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Enzyme regulationi

Inhibited by necrostatin-1.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei51ATPCurated1
Active sitei143Proton acceptor1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi28 – 36ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • identical protein binding Source: MGI
  • NF-kappaB-inducing kinase activity Source: MGI
  • protein complex binding Source: MGI
  • protein kinase activity Source: MGI
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • activation of protein kinase activity Source: UniProtKB
  • amyloid fibril formation Source: UniProtKB
  • I-kappaB kinase/NF-kappaB signaling Source: MGI
  • lymph node development Source: UniProtKB
  • necroptotic process Source: UniProtKB
  • positive regulation of intrinsic apoptotic signaling pathway Source: MGI
  • positive regulation of ligase activity Source: MGI
  • positive regulation of necroptotic process Source: UniProtKB
  • positive regulation of necrotic cell death Source: AgBase
  • positive regulation of NF-kappaB transcription factor activity Source: MGI
  • positive regulation of oxidoreductase activity Source: MGI
  • positive regulation of phosphatase activity Source: MGI
  • positive regulation of protein deacetylation Source: MGI
  • positive regulation of reactive oxygen species metabolic process Source: UniProtKB
  • 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 reactive oxygen species metabolic process Source: MGI
  • regulation of T cell mediated cytotoxicity Source: UniProtKB
  • spleen development Source: UniProtKB
  • T cell differentiation in thymus Source: UniProtKB
  • T cell homeostasis Source: UniProtKB
  • thymus development Source: UniProtKB
  • viral process Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Host-virus interaction, Necrosis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-3295583. TRP channels.
R-MMU-5213460. RIPK1-mediated regulated necrosis.

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
Short name:
mRIP3
Gene namesi
Name:Ripk3
Synonyms:Rip3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 14

Organism-specific databases

MGIiMGI:2154952. Ripk3.

Subcellular locationi

GO - Cellular componenti

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

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Mitochondrion

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi51K → A: Complete loss of induced necrosis. 1
Mutagenesisi111C → A: No effect. 1 Publication1
Mutagenesisi143D → N: Abolishes kinase activity and ability to mediate necroptosis. No autophosphorylation. 2 Publications1
Mutagenesisi230K → A: Slightly affects interaction with MLKL; when associated with A-236. Affects interaction with MLKL; when associated with A-232 and A-236. 1 Publication1
Mutagenesisi231T → A: Abolishes ability to mediate necroptosis. 1 Publication1
Mutagenesisi232S → A: Abolishes ability to mediate necroptosis. Affects interaction with MLKL; when associated with A-230 and A-236. 3 Publications1
Mutagenesisi236E → A: Slightly affects interaction with MLKL; when associated with A-230. Affects interaction with MLKL; when associated with A-230 and A-232. 1 Publication1
Mutagenesisi459 – 462PPRT → AAAA: Complete loss of induced necrosis. 4

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000866111 – 486Receptor-interacting serine/threonine-protein kinase 3Add BLAST486

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2Phosphoserine1 Publication1
Modified residuei165Phosphoserine1 Publication1
Modified residuei204Phosphoserine; by autocatalysisBy similarity1
Modified residuei231Phosphothreonine1 Publication1
Modified residuei232Phosphoserine1 Publication1
Modified residuei257Phosphothreonine1 Publication1
Modified residuei304Phosphoserine1 Publication1
Modified residuei326Phosphoserine1 Publication1
Modified residuei338Phosphothreonine1 Publication1
Modified residuei353Phosphoserine1 Publication1
Modified residuei369Phosphoserine1 Publication1
Modified residuei380Phosphoserine1 Publication1
Modified residuei392Phosphothreonine1 Publication1
Modified residuei477Omega-N-methylarginineCombined sources1

Post-translational modificationi

RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylation of Ser-204 plays a role in the necroptotic function of RIPK3. Phosphorylation at Ser-232 is required for binding MLKL.1 Publication
Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B.By similarity

Keywords - PTMi

Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9QZL0.
MaxQBiQ9QZL0.
PaxDbiQ9QZL0.
PeptideAtlasiQ9QZL0.
PRIDEiQ9QZL0.

PTM databases

iPTMnetiQ9QZL0.
PhosphoSitePlusiQ9QZL0.

Expressioni

Tissue specificityi

Expressed in embryo and in adult spleen, liver, testis, heart, brain and lung.

Gene expression databases

BgeeiENSMUSG00000022221.
CleanExiMM_RIPK3.
ExpressionAtlasiQ9QZL0. baseline and differential.
GenevisibleiQ9QZL0. MM.

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 necroptosis-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 (By similarity). Binds TRAF2 and is recruited to the TNFR-1 signaling complex (By similarity). Interacts with MLKL; the interaction is direct. Interacts with PYGL, GLUL and GLUD1; these interactions result in activation of these metabolic enzymes. Interacts (via RIP homotypic interaction motif) with murid herpesvirus 1 viral inhibitor of RIP activation; this interaction disrupts RIP3-RIP1 interactions characteristic of TNF-alpha induced necroptosis, thereby suppressing this death pathway. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (By similarity). Interacts with ARHGEF2 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
DAXXQ9UER72EBI-2367423,EBI-77321From a different organism.
MlklQ9D2Y43EBI-2367423,EBI-5401970
RIPK1Q135462EBI-2367423,EBI-358507From a different organism.
Ripk1Q608557EBI-2367423,EBI-529119

GO - Molecular functioni

Protein-protein interaction databases

BioGridi208042. 2 interactors.
DIPiDIP-54883N.
IntActiQ9QZL0. 15 interactors.
STRINGi10090.ENSMUSP00000022830.

Structurei

Secondary structure

1486
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi19 – 21Combined sources3
Beta strandi22 – 33Combined sources12
Beta strandi35 – 41Combined sources7
Turni42 – 45Combined sources4
Beta strandi46 – 53Combined sources8
Helixi55 – 65Combined sources11
Beta strandi78 – 81Combined sources4
Beta strandi83 – 85Combined sources3
Beta strandi88 – 96Combined sources9
Helixi103 – 107Combined sources5
Helixi115 – 133Combined sources19
Beta strandi135 – 137Combined sources3
Helixi146 – 148Combined sources3
Beta strandi149 – 151Combined sources3
Beta strandi157 – 159Combined sources3
Helixi164 – 167Combined sources4
Helixi187 – 190Combined sources4
Helixi193 – 195Combined sources3
Helixi205 – 221Combined sources17
Helixi231 – 237Combined sources7
Turni238 – 241Combined sources4
Helixi247 – 249Combined sources3
Beta strandi255 – 257Combined sources3
Helixi260 – 270Combined sources11
Helixi275 – 277Combined sources3
Helixi281 – 295Combined sources15
Helixi296 – 298Combined sources3
Helixi299 – 310Combined sources12

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4M66X-ray2.40A/B1-313[»]
4M69X-ray2.50A1-313[»]
ProteinModelPortaliQ9QZL0.
SMRiQ9QZL0.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini22 – 292Protein kinasePROSITE-ProRule annotationAdd BLAST271

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi440 – 461RIP homotypic interaction motif (RHIM)Add BLAST22

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi352 – 438Pro-richAdd BLAST87

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00550000074536.
HOGENOMiHOG000035101.
HOVERGENiHBG062538.
InParanoidiQ9QZL0.
KOiK08847.
OMAiVTKFMEN.
OrthoDBiEOG091G0DXD.

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]

Sequencei

Sequence statusi: Complete.

Q9QZL0-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSSVKLWPTG ASAVPLVSRE ELKKLEFVGK GGFGVVFRAH HRTWNHDVAV
60 70 80 90 100
KIVNSKKISW EVKAMVNLRN ENVLLLLGVT EDLQWDFVSG QALVTRFMEN
110 120 130 140 150
GSLAGLLQPE CPRPWPLLCR LLQEVVLGMC YLHSLNPPLL HRDLKPSNIL
160 170 180 190 200
LDPELHAKLA DFGLSTFQGG SQSGSGSGSG SRDSGGTLAY LDPELLFDVN
210 220 230 240 250
LKASKASDVY SFGILVWAVL AGREAELVDK TSLIRETVCD RQSRPPLTEL
260 270 280 290 300
PPGSPETPGL EKLKELMIHC WGSQSENRPS FQDCEPKTNE VYNLVKDKVD
310 320 330 340 350
AAVSEVKHYL SQHRSSGRNL SAREPSQRGT EMDCPRETMV SKMLDRLHLE
360 370 380 390 400
EPSGPVPGKC PERQAQDTSV GPATPARTSS DPVAGTPQIP HTLPFRGTTP
410 420 430 440 450
GPVFTETPGP HPQRNQGDGR HGTPWYPWTP PNPMTGPPAL VFNNCSEVQI
460 470 480
GNYNSLVAPP RTTASSSAKY DQAQFGRGRG WQPFHK
Length:486
Mass (Da):53,322
Last modified:February 19, 2014 - v2
Checksum:i31C5EEE77F55778B
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti136N → D in AAF03133 (PubMed:10490590).Curated1
Sequence conflicti136N → D in BAE32636 (PubMed:16141072).Curated1
Sequence conflicti198D → K in AAF03133 (PubMed:10490590).Curated1
Sequence conflicti198D → K in BAE32636 (PubMed:16141072).Curated1
Sequence conflicti198D → N in AAH29210 (PubMed:15489334).Curated1
Sequence conflicti283D → G in BAE32636 (PubMed:16141072).Curated1
Sequence conflicti471D → G in BAE32636 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF178953 mRNA. Translation: AAF03133.1.
AK154505 mRNA. Translation: BAE32636.1.
AC098877 Genomic DNA. No translation available.
CH466535 Genomic DNA. Translation: EDL36236.1.
BC029210 mRNA. Translation: AAH29210.1.
CCDSiCCDS27131.1.
RefSeqiNP_064339.2. NM_019955.2.
UniGeneiMm.46612.

Genome annotation databases

EnsembliENSMUST00000022830; ENSMUSP00000022830; ENSMUSG00000022221.
GeneIDi56532.
KEGGimmu:56532.
UCSCiuc007uav.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF178953 mRNA. Translation: AAF03133.1.
AK154505 mRNA. Translation: BAE32636.1.
AC098877 Genomic DNA. No translation available.
CH466535 Genomic DNA. Translation: EDL36236.1.
BC029210 mRNA. Translation: AAH29210.1.
CCDSiCCDS27131.1.
RefSeqiNP_064339.2. NM_019955.2.
UniGeneiMm.46612.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4M66X-ray2.40A/B1-313[»]
4M69X-ray2.50A1-313[»]
ProteinModelPortaliQ9QZL0.
SMRiQ9QZL0.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi208042. 2 interactors.
DIPiDIP-54883N.
IntActiQ9QZL0. 15 interactors.
STRINGi10090.ENSMUSP00000022830.

PTM databases

iPTMnetiQ9QZL0.
PhosphoSitePlusiQ9QZL0.

Proteomic databases

EPDiQ9QZL0.
MaxQBiQ9QZL0.
PaxDbiQ9QZL0.
PeptideAtlasiQ9QZL0.
PRIDEiQ9QZL0.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000022830; ENSMUSP00000022830; ENSMUSG00000022221.
GeneIDi56532.
KEGGimmu:56532.
UCSCiuc007uav.2. mouse.

Organism-specific databases

CTDi11035.
MGIiMGI:2154952. Ripk3.

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00550000074536.
HOGENOMiHOG000035101.
HOVERGENiHBG062538.
InParanoidiQ9QZL0.
KOiK08847.
OMAiVTKFMEN.
OrthoDBiEOG091G0DXD.

Enzyme and pathway databases

ReactomeiR-MMU-3295583. TRP channels.
R-MMU-5213460. RIPK1-mediated regulated necrosis.

Miscellaneous databases

PROiQ9QZL0.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000022221.
CleanExiMM_RIPK3.
ExpressionAtlasiQ9QZL0. baseline and differential.
GenevisibleiQ9QZL0. MM.

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_MOUSE
AccessioniPrimary (citable) accession number: Q9QZL0
Secondary accession number(s): G3X8V8, Q3U3Z9, Q8K2Y2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 2, 2002
Last sequence update: February 19, 2014
Last modified: November 30, 2016
This is version 142 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. 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.