Q60855 (RIPK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	Ripk1
Synonyms:	Rinp, Rip

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	656 AA.
Sequence status	Complete.
Protein existence	Evidence 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. 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. Ref.4 Ref.8
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 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. Ref.6 Ref.8
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. 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 process	Host-virus interaction Necrosis
Cellular component	Cell membrane Cytoplasm Membrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of necroptosis by extracellular signals Inferred from electronic annotation. Source: Compara apoptotic process Inferred from electronic annotation. Source: Compara cellular protein catabolic process Inferred from sequence or structural similarity. Source: UniProtKB cellular response to tumor necrosis factor Inferred from sequence or structural similarity. Source: UniProtKB induction of apoptosis Inferred from electronic annotation. Source: Compara negative regulation of extrinsic apoptotic signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of intrinsic apoptotic signaling pathway Inferred from mutant phenotype PubMed 20125124. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Inferred from electronic annotation. Source: Compara positive regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of extrinsic apoptotic signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of interleukin-8 production Inferred from electronic annotation. Source: Compara 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 tumor necrosis factor production Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from electronic annotation. Source: Compara protein heterooligomerization Inferred from electronic annotation. Source: Compara protein homooligomerization Inferred from electronic annotation. Source: Compara regulation of ATP:ADP antiporter activity Inferred from electronic annotation. Source: Compara signal transduction Inferred from electronic annotation. Source: InterPro virus-host interaction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	death-inducing signaling complex Inferred from electronic annotation. Source: Compara membrane raft Inferred from electronic annotation. Source: Compara mitochondrion Inferred from electronic annotation. Source: Compara receptor complex Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein kinase activity Inferred from sequence orthology PubMed 15001576. Source: MGI protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HTRA2	O43464	2	EBI-529119,EBI-517086	From a different organism.
Ripk3	Q9QZL0	6	EBI-529119,EBI-2367423

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 656	656	Receptor-interacting serine/threonine-protein kinase 1		PRO_0000086607
Regions
	Domain	17 – 290	274	Protein kinase
	Domain	568 – 654	87	Death
	Nucleotide binding	23 – 31	9	ATP By similarity
	Region	291 – 567	277	Interaction with SQSTM1
	Motif	520 – 536	17	RIP homotypic interaction motif (RHIM)
Sites
	Active site	138	1	Proton acceptor By similarity
	Binding site	46	1	ATP By similarity
Amino acid modifications
	Modified residue	6	1	Phosphoserine By similarity
	Modified residue	25	1	Phosphoserine By similarity
	Modified residue	161	1	Phosphoserine; by RIPK3 and autocatalysis Potential
	Modified residue	166	1	Phosphoserine; by autocatalysis Potential
	Modified residue	304	1	Phosphoserine By similarity
	Modified residue	313	1	Phosphoserine Ref.7
	Modified residue	321	1	Phosphoserine By similarity
	Modified residue	334	1	Phosphoserine By similarity
	Modified residue	383	1	Phosphotyrosine By similarity
Natural variations
	Natural variant	473	1	T → I.
Experimental info
	Sequence conflict	66	1	M → K in BAC27194. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q60855 [UniParc]. Last modified November 1, 1997. Version 1. Checksum: ABB350B523879933	FASTA	656	74,854
	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

References

	« Hide 'large scale' referencesShow '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. , 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]	"The phagosomal proteome in interferon-gamma-activated macrophages." Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P. Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-313, MASS SPECTROMETRY. Tissue: Macrophage.
[8]	"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.
IPI	IPI00121472.
PIR	I49299.
RefSeq	NP_033094.3. NM_009068.3.
UniGene	Mm.374799.
3D structure databases
ProteinModelPortal	Q60855.
SMR	Q60855. Positions 7-319, 577-655.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-34962N.
IntAct	Q60855. 10 interactions.
MINT	MINT-144784.
STRING	10090.ENSMUSP00000021844.
PTM databases
PhosphoSite	Q60855.
Proteomic databases
PaxDb	Q60855.
PRIDE	Q60855.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000021844; ENSMUSP00000021844; ENSMUSG00000021408. ENSMUST00000167374; ENSMUSP00000129831; ENSMUSG00000021408.
GeneID	19766.
KEGG	mmu:19766.
UCSC	uc007qax.1. mouse.
Organism-specific databases
CTD	8737.
MGI	MGI:108212. Ripk1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00550000074536.
HOGENOM	HOG000010270.
HOVERGEN	HBG055612.
InParanoid	Q60855.
KO	K02861.
OMA	SHDPFAQ.
OrthoDB	EOG434W5G.
Enzyme and pathway databases
BRENDA	2.7.10.2. 3474.
Gene expression databases
Bgee	Q60855.
Genevestigator	Q60855.
GermOnline	ENSMUSG00000021408. Mus musculus.
Family and domain databases
Gene3D	1.10.533.10. 1 hit.
InterPro	IPR011029. DEATH-like_dom. IPR000488. Death_domain. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR025735. RHIM_dom. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00531. Death. 1 hit. PF07714. Pkinase_Tyr. 1 hit. PF12721. RHIM. 1 hit. [Graphical view]
PRINTS	PR00109. TYRKINASE.
SMART	SM00005. DEATH. 1 hit. [Graphical view]
SUPFAM	SSF47986. DEATH_like. 1 hit. SSF56112. Kinase_like. 1 hit.
PROSITE	PS50017. DEATH_DOMAIN. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	297220.
SOURCE	Search...

Entry information

Entry name

RIPK1_MOUSE

Accession

Primary (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:	May 1, 2013
This is version 130 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program