Reviewed, UniProtKB/Swiss-Prot Q13546 (RIPK1_HUMAN)

Names and origin

Protein names

Recommended name:
    Receptor-interacting serine/threonine-protein kinase 1
    EC=2.7.11.1
Alternative name(s):
    Serine/threonine-protein kinase RIP
    Cell death protein RIP
    Receptor-interacting protein

Gene names

Name:	RIPK1
Synonyms:	RIP

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	671 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Promotes apoptosis and activation of NF-kappa-B. Required for TNFRSF1A mediated activation of NF-kappa-B.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	Binds to the death domain of TNFRSF6 and TRADD. Is recruited by TRADD to TNFRSF1A in a TNF-dependent process. Binds RIPK3, UBCE7IP1 isoform 3 (ZIN), EGFR, IKBKG, TRAF1, TRAF2 and TRAF3. Interacts with BNLF1. Interacts with SQSTM1 upon TNF-alpha stimulation. May interacts with MAVS/IPS1. Ref.1 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15
Subcellular location	Cytoplasm.
Post-translational modification	Proteolytically cleaved by caspase-8 during TNF-induced apoptosis. Cleavage abolishes NF-kappa-B activation and enhances pro-apototic signaling through the TRADD-FADD interaction. Ref.7 Autophosphorylated on serine and threonine residues. Ref.1 Ref.14 Ref.16
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	Apoptosis
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	I-kappaB kinase/NF-kappaB cascade Inferred from Experiment. Source: Reactome activation of JUN kinase activity Traceable author statement. Source: UniProtKB activation of pro-apoptotic gene products Inferred from Experiment. Source: Reactome induction of apoptosis Ref.1 Ref.7 Inferred from mutant phenotype. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from expression pattern. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Ref.1 Ref.7 Inferred from mutant phenotype. Source: UniProtKB positive regulation of anti-apoptosis Traceable author statement. Source: UniProtKB positive regulation of necrotic cell death Inferred from mutant phenotype. Source: UniProtKB protein amino acid autophosphorylation Ref.1 Inferred from direct assay. Source: UniProtKB regulation of oxygen and reactive oxygen species metabolic process Traceable author statement. Source: UniProtKB response to tumor necrosis factor Ref.7 Inferred from mutant phenotype. Source: UniProtKB tumor necrosis factor-mediated signaling pathway Ref.1 Inferred by curator. Source: UniProtKB
Cellular component	cytosol Inferred from Experiment. Source: Reactome death-inducing signaling complex Inferred from direct assay. Source: UniProtKB mitochondrion Inferred from direct assay. Source: UniProtKB receptor complex Ref.1 Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW death domain binding Ref.1 Inferred from physical interaction. Source: UniProtKB death receptor binding Ref.6 Inferred from physical interaction. Source: UniProtKB protein serine/threonine kinase activity Ref.1 Inferred from direct assay. Source: UniProtKB protein tyrosine kinase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CASP8	Q14790	1	EBI-358507,EBI-78060
CCDC50	Q8IVM0	2	EBI-358507,EBI-723996
CSNK1A1	P48729	4	EBI-358507,EBI-1383726
IKBKG	Q9Y6K9	1	EBI-358507,EBI-81279
Map3k8	Q07174	1	EBI-358507,EBI-309771	From a different organism.
Nfkb1	P25799	1	EBI-358507,EBI-643958	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 671	671	Receptor-interacting serine/threonine-protein kinase 1		PRO_0000086606
Regions
	Domain	17 – 289	273	Protein kinase
	Domain	583 – 669	87	Death
	Nucleotide binding	23 – 31	9	ATP By similarity
	Region	290 – 582	293	Interaction with SQSTM1
	Compositional bias	411 – 414	4	Poly-Arg
Sites
	Active site	138	1	Proton acceptor By similarity
	Binding site	49	1	ATP By similarity
	Site	324 – 325	2	Cleavage; by caspase-8
Amino acid modifications
	Modified residue	320	1	Phosphoserine Ref.16
	Modified residue	384	1	Phosphotyrosine Ref.14
	Modified residue	387	1	Phosphotyrosine Ref.14
	Modified residue	389	1	Phosphoserine Ref.14
Natural variations
	Natural variant	64	1	A → V in a colorectal adenocarcinoma sample; somatic mutation. Ref.17		VAR_041039
	Natural variant	81	1	V → I in a colorectal adenocarcinoma sample; somatic mutation. Ref.17		VAR_041040
	Natural variant	220	1	A → V in a colorectal adenocarcinoma sample; somatic mutation. Ref.17		VAR_041041
	Natural variant	234	1	E → K: dbSNP rs17548383. Ref.3		VAR_021109
	Natural variant	404	1	A → S Ref.17		VAR_041042
	Natural variant	443	1	A → V Ref.17		VAR_041043
	Natural variant	569	1	A → V Ref.17		VAR_041044
Experimental info
	Mutagenesis	45	1	K → A: Abolishes kinase activity. Ref.1
	Mutagenesis	324	1	D → K: Abolishes cleavage by caspase-8. Ref.7
	Sequence conflict	438	1	A → V Ref.1
	Sequence conflict	438	1	A → V Ref.6
	Sequence conflict	514	1	T → S in AAC50137. Ref.6

Sequences

	Sequence		Length	Mass (Da)
	Q13546-1 [UniParc]. Last modified February 1, 2005. Version 3. Checksum: 976E2428D525A9B2	FASTA	671	75,931
	10 20 30 40 50 60 MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG PNCIEHNEAL 70 80 90 100 110 120 LEEAKMMNRL RHSRVVKLLG VIIEEGKYSL VMEYMEKGNL MHVLKAEMST PLSVKGRIIL 130 140 150 160 170 180 EIIEGMCYLH GKGVIHKDLK PENILVDNDF HIKIADLGLA SFKMWSKLNN EEHNELREVD 190 200 210 220 230 240 GTAKKNGGTL YYMAPEHLND VNAKPTEKSD VYSFAVVLWA IFANKEPYEN AICEQQLIMC 250 260 270 280 290 300 IKSGNRPDVD DITEYCPREI ISLMKLCWEA NPEARPTFPG IEEKFRPFYL SQLEESVEED 310 320 330 340 350 360 VKSLKKEYSN ENAVVKRMQS LQLDCVAVPS SRSNSATEQP GSLHSSQGLG MGPVEESWFA 370 380 390 400 410 420 PSLEHPQEEN EPSLQSKLQD EANYHLYGSR MDRQTKQQPR QNVAYNREEE RRRRVSHDPF 430 440 450 460 470 480 AQQRPYENFQ NTEGKGTAYS SAASHGNAVH QPSGLTSQPQ VLYQNNGLYS SHGFGTRPLD 490 500 510 520 530 540 PGTAGPRVWY RPIPSHMPSL HNIPVPETNY LGNTPTMPFS SLPPTDESIK YTIYNSTGIQ 550 560 570 580 590 600 IGAYNYMEIG GTSSSLLDST NTNFKEEPAA KYQAIFDNTT SLTDKHLDPI RENLGKHWKN 610 620 630 640 650 660 CARKLGFTQS QIDEIDHDYE RDGLKEKVYQ MLQKWVMREG IKGATVGKLA QALHQCSRID 670 LLSSLIYVSQ N

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex." Hsu H., Huang J., Shu H.-B., Baichwal V.R., Goeddel D.V. Immunity 4:387-396(1996) [PubMed: 8612133] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], AUTOPHOSPHORYLATION, MUTAGENESIS OF LYS-45, INTERACTION WITH TRADD; TRAF1; TRAF2 AND TRAF3. Tissue: Umbilical vein endothelial cell.
[2]	Huang J., Hsu H., Baichwal V.R., Goeddel D.V. Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO 120.
[3]	SeattleSNPs variation discovery resource Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LYS-234.
[4]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[6]	"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: 7538908] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 300-671. Tissue: Leukemic T-cell.
[7]	"Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis." Lin Y., Devin A., Rodriguez Y., Liu Z.-G. Genes Dev. 13:2514-2526(1999) [PubMed: 10521396] [Abstract] Cited for: CLEAVAGE BY CASPASE-8, MUTAGENESIS OF ASP-324.
[8]	"The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation." Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J. EMBO J. 18:3044-3053(1999) [PubMed: 10356400] [Abstract] Cited for: INTERACTION WITH SQSTM1 AND TRAF2, DOMAIN.
[9]	"RIP3, a novel apoptosis-inducing kinase." Sun X., Lee J., Navas T., Baldwin D.T., Stewart T.A., Dixit V.M. J. Biol. Chem. 274:16871-16875(1999) [PubMed: 10358032] [Abstract] Cited for: INTERACTION WITH RIPK3.
[10]	"The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the tumor necrosis factor receptor-associated proteins TRADD and receptor-interacting protein (RIP) but does not induce apoptosis or require RIP for NF-kappaB activation." Izumi K.M., Cahir McFarland E., Ting A.T., Riley E.A., Seed B., Kieff E.D. Mol. Cell. Biol. 19:5759-5767(1999) [PubMed: 10409763] [Abstract] Cited for: INTERACTION WITH BNLF1.
[11]	"Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis." Li Y., Kang J., Friedman J., Tarassishin L., Ye J., Kovalenko A., Wallach D., Horwitz M.S. Proc. Natl. Acad. Sci. U.S.A. 96:1042-1047(1999) [PubMed: 9927690] [Abstract] Cited for: INTERACTION WITH IKBKG.
[12]	"The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome." Habib A.A., Chatterjee S., Park S.-K., Ratan R.R., Lefebvre S., Vartanian T. J. Biol. Chem. 276:8865-8874(2001) [PubMed: 11116146] [Abstract] Cited for: INTERACTION WITH EGFR.
[13]	"A novel zinc finger protein interacts with receptor-interacting protein (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B activation." Chen D., Li X., Zhai Z., Shu H.-B. J. Biol. Chem. 277:15985-15991(2002) [PubMed: 11854271] [Abstract] Cited for: INTERACTION WITH UBCE7IP1.
[14]	"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry." Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C. Anal. Chem. 76:2763-2772(2004) [PubMed: 15144186] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-384; TYR-387 AND SER-389, MASS SPECTROMETRY. Tissue: T-cell.
[15]	"IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction." Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H., Ishii K.J., Takeuchi O., Akira S. Nat. Immunol. 6:981-988(2005) [PubMed: 16127453] [Abstract] Cited for: INTERACTION WITH MAVS.
[16]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, MASS SPECTROMETRY.
[17]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-64; ILE-81; VAL-220; SER-404; VAL-443 AND VAL-569.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	U50062 mRNA. Translation: AAC32232.1. AY682848 Genomic DNA. Translation: AAT74626.1. AL031963 Genomic DNA. Translation: CAD70625.1. BC126254 mRNA. Translation: AAI26255.1. BC126256 mRNA. Translation: AAI26257.1. U25994 mRNA. Translation: AAC50137.1.
IPI	IPI00013773.
PIR	T09479.
RefSeq	NP_003795.2.
UniGene	Hs.519842
3D structure databases
HSSP	HSSP built from PDB template 1BYG based on UniProtKB P41240.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP:433N.
IntAct	Q13546. 27 interactions.
PTM databases
PhosphoSite	Q13546.
Proteomic databases
PRIDE	Q13546.
Genome annotation databases
Ensembl	ENSG00000137275. Homo sapiens. [Contig view]
GeneID	8737.
KEGG	hsa:8737.
Organism-specific databases
GeneCards	GC06P003022.
H-InvDB	HIX0005535.
HGNC	HGNC:10019. RIPK1.
HPA	CAB010302. HPA015257.
MIM	603453. gene.
PharmGKB	PA34394.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q13546.
HOVERGEN	Q13546.
OMA	Q13546. SHDPFAQ.
Enzyme and pathway databases
BRENDA	2.7.10.2. 247. 2.7.11.1. 247.
Pathway_Interaction_DB	caspase_pathway. Caspase cascade in apoptosis. ceramidepathway. Ceramide signaling pathway. faspathway. FAS signaling pathway (CD95). hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha. p38alphabetapathway. Regulation of p38-alpha and p38-beta. tnfpathway. TNF receptor signaling pathway. trail_pathway. TRAIL signaling pathway.
Reactome	REACT_578. Apoptosis. REACT_6900. Signaling in Immune system.
Gene expression databases
ArrayExpress	Q13546.
Bgee	Q13546.
CleanEx	HS_RIPK1.
Family and domain databases
InterPro	IPR000488. Death. IPR011029. DEATH-like. IPR000719. Prot_kinase_core. IPR017442. Se/Thr_pkinase-rel. IPR008271. Ser_thr_pkin_AS. IPR001245. Tyr_pkinase. [Graphical view]
Gene3D	G3DSA:1.10.533.10. DEATH_like. 1 hit.
Pfam	PF00531. Death. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view]
PRINTS	PR00109. TYRKINASE.
ProDom	PD000001. Prot_kinase. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00005. DEATH. 1 hit. [Graphical view]
PROSITE	PS50017. DEATH_DOMAIN. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	32775.
PMAP-CutDB	Q13546.
SOURCE	Search...

Entry information

Entry name

RIPK1_HUMAN

Accession

Primary (citable) accession number: Q13546
Secondary accession number(s): A0AV89, Q13180

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	February 1, 2005
Last modified:	June 16, 2009
This is version 95 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)