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Q60855 (RIPK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 141. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:Ripk1
Synonyms:Rinp, Rip
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length656 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.4 Ref.7

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

Inhibited by necrostatin-1 By similarity.

Subunit structure

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. Ref.6 Ref.7

Subcellular location

Cytoplasm. Cell membrane.

Tissue specificity

Found at low levels in all tissues.

Induction

In concanavalin A-treated splenocytes.

Domain

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.

Post-translational modification

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.

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.

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 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 By similarity. 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.

Sequence similarities

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Contains 1 death domain.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processHost-virus interaction
Necrosis
   Cellular componentCell membrane
Cytoplasm
Membrane
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processT cell apoptotic process

Inferred from mutant phenotype PubMed 21876153. Source: UniProtKB

amyloid fibril formation

Inferred from sequence or structural similarity. Source: UniProtKB

apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

cellular protein catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to growth factor stimulus

Inferred from mutant phenotype PubMed 20125124. Source: UniProtKB

cellular response to tumor necrosis factor

Inferred from sequence or structural similarity. Source: UniProtKB

extrinsic apoptotic signaling pathway

Inferred from electronic annotation. Source: Ensembl

necroptotic process

Inferred from genetic interaction PubMed 19498109PubMed 21052097PubMed 22037414. Source: MGI

necroptotic signaling pathway

Inferred from mutant phenotype PubMed 21876153. Source: UniProtKB

negative regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from electronic annotation. Source: Ensembl

negative regulation of extrinsic apoptotic signaling pathway

Inferred from genetic interaction PubMed 22089168. Source: MGI

negative regulation of extrinsic apoptotic signaling pathway in absence of ligand

Inferred from mutant phenotype PubMed 20125124. Source: UniProtKB

peptidyl-serine autophosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of JNK cascade

Inferred from mutant phenotype PubMed 20125124. Source: UniProtKB

positive regulation of MAPK cascade

Inferred from mutant phenotype PubMed 20125124. Source: UniProtKB

positive regulation of NF-kappaB transcription factor activity

Inferred from mutant phenotype PubMed 20125124. Source: UniProtKB

positive regulation of apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of extrinsic apoptotic signaling pathway

Inferred from genetic interaction PubMed 19498109. Source: MGI

positive regulation of interleukin-8 production

Inferred from electronic annotation. Source: Ensembl

positive regulation of macrophage differentiation

Inferred from electronic annotation. Source: Ensembl

positive regulation of necroptotic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of phosphorylation

Inferred from mutant phenotype PubMed 21052097. Source: UniProtKB

positive regulation of protein phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of transferase activity

Inferred from genetic interaction PubMed 19498109. Source: MGI

positive regulation of tumor necrosis factor production

Inferred from electronic annotation. Source: Ensembl

protein heterooligomerization

Inferred from sequence or structural similarity. Source: UniProtKB

protein homooligomerization

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of ATP:ADP antiporter activity

Inferred from electronic annotation. Source: Ensembl

regulation of reactive oxygen species metabolic process

Inferred from mutant phenotype PubMed 21052097. Source: MGI

ripoptosome assembly

Inferred from sequence or structural similarity. Source: UniProtKB

ripoptosome assembly involved in necroptotic process

Inferred from genetic interaction PubMed 21052097. Source: MGI

viral process

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentdeath-inducing signaling complex

Inferred from electronic annotation. Source: Ensembl

membrane raft

Inferred from electronic annotation. Source: Ensembl

mitochondrion

Inferred from electronic annotation. Source: Ensembl

receptor complex

Inferred from electronic annotation. Source: Ensembl

ripoptosome

Inferred from direct assay PubMed 23201684. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

HTRA2O434642EBI-529119,EBI-517086From a different organism.
Ripk3Q9QZL07EBI-529119,EBI-2367423
Tnfrsf1aP251183EBI-529119,EBI-518014

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 656656Receptor-interacting serine/threonine-protein kinase 1
PRO_0000086607

Regions

Domain17 – 290274Protein kinase
Domain568 – 65487Death
Nucleotide binding23 – 319ATP By similarity
Region291 – 567277Interaction with SQSTM1
Motif520 – 53617RIP homotypic interaction motif (RHIM)

Sites

Active site1381Proton acceptor By similarity
Binding site461ATP By similarity

Amino acid modifications

Modified residue61Phosphoserine By similarity
Modified residue251Phosphoserine By similarity
Modified residue1611Phosphoserine; by RIPK3 and autocatalysis Potential
Modified residue1661Phosphoserine; by autocatalysis Potential
Modified residue3041Phosphoserine By similarity
Modified residue3211Phosphoserine By similarity
Modified residue3341Phosphoserine By similarity
Modified residue3831Phosphotyrosine By similarity

Natural variations

Natural variant4731T → I.

Experimental info

Sequence conflict661M → K in BAC27194. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q60855 [UniParc].

Last modified November 1, 1997. Version 1.
Checksum: ABB350B523879933

FASTA65674,854
        10         20         30         40         50         60 
MQPDMSLDNI KMASSDLLEK TDLDSGGFGK VSLCYHRSHG FVILKKVYTG PNRAEYNEVL 

        70         80         90        100        110        120 
LEEGKMMHRL RHSRVVKLLG IIIEEGNYSL VMEYMEKGNL MHVLKTQIDV PLSLKGRIIV 

       130        140        150        160        170        180 
EAIEGMCYLH DKGVIHKDLK PENILVDRDF HIKIADLGVA SFKTWSKLTK EKDNKQKEVS 

       190        200        210        220        230        240 
STTKKNNGGT LYYMAPEHLN DINAKPTEKS DVYSFGIVLW AIFAKKEPYE NVICTEQFVI 

       250        260        270        280        290        300 
CIKSGNRPNV EEILEYCPRE IISLMERCWQ AIPEDRPTFL GIEEEFRPFY LSHFEEYVEE 

       310        320        330        340        350        360 
DVASLKKEYP DQSPVLQRMF SLQHDCVPLP PSRSNSEQPG SLHSSQGLQM GPVEESWFSS 

       370        380        390        400        410        420 
SPEYPQDEND RSVQAKLQEE ASYHAFGIFA EKQTKPQPRQ NEAYNREEER KRRVSHDPFA 

       430        440        450        460        470        480 
QQRARENIKS AGARGHSDPS TTSRGIAVQQ LSWPATQTVW NNGLYNQHGF GTTGTGVWYP 

       490        500        510        520        530        540 
PNLSQMYSTY KTPVPETNIP GSTPTMPYFS GPVADDLIKY TIFNSSGIQI GNHNYMDVGL 

       550        560        570        580        590        600 
NSQPPNNTCK EESTSRHQAI FDNTTSLTDE HLNPIRENLG RQWKNCARKL GFTESQIDEI 

       610        620        630        640        650 
DHDYERDGLK EKVYQMLQKW LMREGTKGAT VGKLAQALHQ CCRIDLLNHL IRASQS 

« Hide

References

« Hide 'large scale' references
[1]"RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death."
Stanger B.Z., Leder P., Lee T.-H., Kim E., Seed B.
Cell 81:513-523(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: C57BL/6 X CBA.
Tissue: Thymus.
[2]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J and NOD.
Tissue: Spleen and Thymus.
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6.
Tissue: Brain and Liver.
[4]"The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation."
Hur G.M., Lewis J., Yang Q., Lin Y., Nakano H., Nedospasov S., Liu Z.G.
Genes Dev. 17:873-882(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[5]"RIP1, a kinase on the crossroads of a cell's decision to live or die."
Festjens N., Vanden Berghe T., Cornelis S., Vandenabeele P.
Cell Death Differ. 14:400-410(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[6]"Cytomegalovirus M45 cell death suppression requires receptor-interacting protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with RIP1."
Upton J.W., Kaiser W.J., Mocarski E.S.
J. Biol. Chem. 283:16966-16970(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MURID HERPESVIRUS 1 VIRAL INHIBITOR OF RIP ACTIVATION.
[7]"DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB."
Rebsamen M., Heinz L.X., Meylan E., Michallet M.C., Schroder K., Hofmann K., Vazquez J., Benedict C.A., Tschopp J.
EMBO Rep. 10:916-922(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH ZBP1.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
PIRI49299.
RefSeqNP_033094.3. NM_009068.3.
XP_006516670.1. XM_006516607.1.
XP_006516671.1. XM_006516608.1.
XP_006516672.1. XM_006516609.1.
UniGeneMm.374799.

3D structure databases

ProteinModelPortalQ60855.
SMRQ60855. Positions 7-339, 577-655.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid202896. 16 interactions.
DIPDIP-34962N.
IntActQ60855. 12 interactions.
MINTMINT-144784.
STRING10090.ENSMUSP00000021844.

PTM databases

PhosphoSiteQ60855.

Proteomic databases

PaxDbQ60855.
PRIDEQ60855.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000021844; ENSMUSP00000021844; ENSMUSG00000021408.
ENSMUST00000167374; ENSMUSP00000129831; ENSMUSG00000021408.
GeneID19766.
KEGGmmu:19766.
UCSCuc007qax.1. mouse.

Organism-specific databases

CTD8737.
MGIMGI:108212. Ripk1.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00550000074536.
HOGENOMHOG000010270.
HOVERGENHBG055612.
InParanoidQ60855.
KOK02861.
OMASHDPFAQ.
OrthoDBEOG7MPRDN.
PhylomeDBQ60855.
TreeFamTF106506.

Enzyme and pathway databases

BRENDA2.7.10.2. 3474.

Gene expression databases

BgeeQ60855.
GenevestigatorQ60855.

Family and domain databases

Gene3D1.10.533.10. 1 hit.
InterProIPR011029. 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]
PfamPF00531. Death. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF12721. RHIM. 1 hit.
[Graphical view]
PRINTSPR00109. TYRKINASE.
SMARTSM00005. DEATH. 1 hit.
[Graphical view]
SUPFAMSSF47986. SSF47986. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS50017. DEATH_DOMAIN. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio297220.
PROQ60855.
SOURCESearch...

Entry information

Entry nameRIPK1_MOUSE
AccessionPrimary (citable) accession number: Q60855
Secondary accession number(s): Q3U0J3, Q8CD90
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: April 16, 2014
This is version 141 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot