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Protein

Receptor-interacting serine/threonine-protein kinase 1

Gene

Ripk1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex (By similarity). Interacts with ARHGEF2 (By similarity).By similarity2 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Inhibited by necrostatin-1.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei46ATPPROSITE-ProRule annotation1
Active sitei138Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi23 – 31ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

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

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-3295583. TRP channels.
R-MMU-3371378. Regulation by c-FLIP.
R-MMU-5213460. RIPK1-mediated regulated necrosis.
R-MMU-5218900. CASP8 activity is inhibited.
R-MMU-5357786. TNFR1-induced proapoptotic signaling.
R-MMU-5357905. Regulation of TNFR1 signaling.
R-MMU-5357956. TNFR1-induced NFkappaB signaling pathway.
R-MMU-5689880. Ub-specific processing proteases.
R-MMU-5689896. Ovarian tumor domain proteases.
R-MMU-69416. Dimerization of procaspase-8.
R-MMU-75893. TNF signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Receptor-interacting serine/threonine-protein kinase 1 (EC:2.7.11.1)
Alternative name(s):
Cell death protein RIP
Receptor-interacting protein 1
Short name:
RIP-1
Serine/threonine-protein kinase RIP
Gene namesi
Name:Ripk1
Synonyms:Rinp, Rip
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:108212. Ripk1.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000866071 – 656Receptor-interacting serine/threonine-protein kinase 1Add BLAST656

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei6PhosphoserineBy similarity1
Modified residuei25PhosphoserineBy similarity1
Modified residuei161Phosphoserine; by RIPK3 and autocatalysisSequence analysis1
Modified residuei166Phosphoserine; by autocatalysisSequence analysis1
Modified residuei304PhosphoserineBy similarity1
Modified residuei313PhosphoserineCombined sources1
Modified residuei321PhosphoserineCombined sources1
Modified residuei334PhosphoserineBy similarity1
Modified residuei383PhosphotyrosineBy similarity1

Post-translational modificationi

Proteolytically cleaved by caspase-8 during TNF-induced apoptosis. Cleavage abolishes NF-kappa-B activation and enhances pro-apoptotic signaling through the TRADD-FADD interaction (By similarity).By similarity
RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex (By similarity).By similarity
Ubiquitinated by 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin. Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex. Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal degradation and consequently down-regulates TNF-alpha-induced NFkappa-B signaling. 'Lys-48'-linked polyubiquitination by RFFL or RNF34 also promotes proteasomal degradation and negatively regulates TNF-alpha-induced NFkappa-B signaling. Linear polyubiquitinated; the head-to-tail polyubiquitination is mediated by the LUBAC complex. LPS-mediated activation of NF-kappa-B. Also ubiquitinated with 'Lys-11'-linked chains. 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

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ60855.
MaxQBiQ60855.
PaxDbiQ60855.
PeptideAtlasiQ60855.
PRIDEiQ60855.

PTM databases

iPTMnetiQ60855.
PhosphoSitePlusiQ60855.

Expressioni

Tissue specificityi

Found at low levels in all tissues.

Inductioni

In concanavalin A-treated splenocytes.

Gene expression databases

BgeeiENSMUSG00000021408.
ExpressionAtlasiQ60855. baseline and differential.
GenevisibleiQ60855. MM.

Interactioni

Subunit structurei

Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif). 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 (via kinase domain) with DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha-dependent manner (By similarity). Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process. Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3. Interacts with BNLF1. Interacts with SQSTM1 upon TNF-alpha stimulation. May interact with MAVS/IPS1. Interacts with ZFAND5. Interacts with RBCK1 (By similarity). Interacts (via RIP homotypic interaction motif) with murid herpesvirus 1 viral inhibitor of RIP activation; this interaction inhibits RIPK1 ubiquitination. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (By similarity). Interacts with ARHGEF2 (By similarity). Interacts (via protein kinase domain) with RFFL; involved in RIPK1 ubiquitination (By similarity). Interacts with RNF34; involved in RIPK1 ubiquitination (By similarity). Interacts with ZBP1. Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (By similarity).By similarity1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
HTRA2O434642EBI-529119,EBI-517086From a different organism.
Ripk3Q9QZL07EBI-529119,EBI-2367423
Tnfrsf1aP251183EBI-529119,EBI-518014

GO - Molecular functioni

Protein-protein interaction databases

BioGridi202896. 19 interactors.
DIPiDIP-34962N.
IntActiQ60855. 14 interactors.
MINTiMINT-144784.
STRINGi10090.ENSMUSP00000021844.

Structurei

3D structure databases

ProteinModelPortaliQ60855.
SMRiQ60855.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini17 – 290Protein kinasePROSITE-ProRule annotationAdd BLAST274
Domaini568 – 654DeathPROSITE-ProRule annotationAdd BLAST87

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni291 – 567Interaction with SQSTM1Add BLAST277

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi520 – 536RIP homotypic interaction motif (RHIM)Add BLAST17

Domaini

Contains a C-terminal death domain (DD) that engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling.

Sequence similaritiesi

Contains 1 death domain.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00550000074536.
HOGENOMiHOG000010270.
HOVERGENiHBG055612.
InParanoidiQ60855.
KOiK02861.
OMAiVVKRMQS.
OrthoDBiEOG091G0479.
PhylomeDBiQ60855.
TreeFamiTF106506.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR025735. RHIM_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00531. Death. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF12721. RHIM. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00005. DEATH. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50017. DEATH_DOMAIN. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q60855-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MQPDMSLDNI KMASSDLLEK TDLDSGGFGK VSLCYHRSHG FVILKKVYTG
60 70 80 90 100
PNRAEYNEVL LEEGKMMHRL RHSRVVKLLG IIIEEGNYSL VMEYMEKGNL
110 120 130 140 150
MHVLKTQIDV PLSLKGRIIV EAIEGMCYLH DKGVIHKDLK PENILVDRDF
160 170 180 190 200
HIKIADLGVA SFKTWSKLTK EKDNKQKEVS STTKKNNGGT LYYMAPEHLN
210 220 230 240 250
DINAKPTEKS DVYSFGIVLW AIFAKKEPYE NVICTEQFVI CIKSGNRPNV
260 270 280 290 300
EEILEYCPRE IISLMERCWQ AIPEDRPTFL GIEEEFRPFY LSHFEEYVEE
310 320 330 340 350
DVASLKKEYP DQSPVLQRMF SLQHDCVPLP PSRSNSEQPG SLHSSQGLQM
360 370 380 390 400
GPVEESWFSS SPEYPQDEND RSVQAKLQEE ASYHAFGIFA EKQTKPQPRQ
410 420 430 440 450
NEAYNREEER KRRVSHDPFA QQRARENIKS AGARGHSDPS TTSRGIAVQQ
460 470 480 490 500
LSWPATQTVW NNGLYNQHGF GTTGTGVWYP PNLSQMYSTY KTPVPETNIP
510 520 530 540 550
GSTPTMPYFS GPVADDLIKY TIFNSSGIQI GNHNYMDVGL NSQPPNNTCK
560 570 580 590 600
EESTSRHQAI FDNTTSLTDE HLNPIRENLG RQWKNCARKL GFTESQIDEI
610 620 630 640 650
DHDYERDGLK EKVYQMLQKW LMREGTKGAT VGKLAQALHQ CCRIDLLNHL

IRASQS
Length:656
Mass (Da):74,854
Last modified:November 1, 1997 - v1
Checksum:iABB350B523879933
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti66M → K in BAC27194 (PubMed:16141072).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti473T → I.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U25995 mRNA. Translation: AAB60487.1.
AK030959 mRNA. Translation: BAC27194.1.
AK156803 mRNA. Translation: BAE33860.1.
BC050905 mRNA. Translation: AAH50905.2.
BC054542 mRNA. Translation: AAH54542.1.
BC058162 mRNA. Translation: AAH58162.1.
CCDSiCCDS26443.1.
PIRiI49299.
RefSeqiNP_033094.3. NM_009068.3.
XP_006516670.1. XM_006516607.3.
XP_006516672.1. XM_006516609.3.
UniGeneiMm.374799.

Genome annotation databases

EnsembliENSMUST00000021844; ENSMUSP00000021844; ENSMUSG00000021408.
ENSMUST00000167374; ENSMUSP00000129831; ENSMUSG00000021408.
GeneIDi19766.
KEGGimmu:19766.
UCSCiuc007qax.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U25995 mRNA. Translation: AAB60487.1.
AK030959 mRNA. Translation: BAC27194.1.
AK156803 mRNA. Translation: BAE33860.1.
BC050905 mRNA. Translation: AAH50905.2.
BC054542 mRNA. Translation: AAH54542.1.
BC058162 mRNA. Translation: AAH58162.1.
CCDSiCCDS26443.1.
PIRiI49299.
RefSeqiNP_033094.3. NM_009068.3.
XP_006516670.1. XM_006516607.3.
XP_006516672.1. XM_006516609.3.
UniGeneiMm.374799.

3D structure databases

ProteinModelPortaliQ60855.
SMRiQ60855.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi202896. 19 interactors.
DIPiDIP-34962N.
IntActiQ60855. 14 interactors.
MINTiMINT-144784.
STRINGi10090.ENSMUSP00000021844.

PTM databases

iPTMnetiQ60855.
PhosphoSitePlusiQ60855.

Proteomic databases

EPDiQ60855.
MaxQBiQ60855.
PaxDbiQ60855.
PeptideAtlasiQ60855.
PRIDEiQ60855.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000021844; ENSMUSP00000021844; ENSMUSG00000021408.
ENSMUST00000167374; ENSMUSP00000129831; ENSMUSG00000021408.
GeneIDi19766.
KEGGimmu:19766.
UCSCiuc007qax.1. mouse.

Organism-specific databases

CTDi8737.
MGIiMGI:108212. Ripk1.

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00550000074536.
HOGENOMiHOG000010270.
HOVERGENiHBG055612.
InParanoidiQ60855.
KOiK02861.
OMAiVVKRMQS.
OrthoDBiEOG091G0479.
PhylomeDBiQ60855.
TreeFamiTF106506.

Enzyme and pathway databases

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-3295583. TRP channels.
R-MMU-3371378. Regulation by c-FLIP.
R-MMU-5213460. RIPK1-mediated regulated necrosis.
R-MMU-5218900. CASP8 activity is inhibited.
R-MMU-5357786. TNFR1-induced proapoptotic signaling.
R-MMU-5357905. Regulation of TNFR1 signaling.
R-MMU-5357956. TNFR1-induced NFkappaB signaling pathway.
R-MMU-5689880. Ub-specific processing proteases.
R-MMU-5689896. Ovarian tumor domain proteases.
R-MMU-69416. Dimerization of procaspase-8.
R-MMU-75893. TNF signaling.

Miscellaneous databases

ChiTaRSiRipk1. mouse.
PROiQ60855.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000021408.
ExpressionAtlasiQ60855. baseline and differential.
GenevisibleiQ60855. MM.

Family and domain databases

Gene3Di1.10.533.10. 1 hit.
InterProiIPR011029. DEATH-like_dom.
IPR000488. Death_domain.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR025735. RHIM_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00531. Death. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF12721. RHIM. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00005. DEATH. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50017. DEATH_DOMAIN. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiRIPK1_MOUSE
AccessioniPrimary (citable) accession number: Q60855
Secondary accession number(s): Q3U0J3, Q8CD90
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: November 2, 2016
This is version 167 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. 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.