Q9Y572 (RIPK3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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

Gene names

Name:	RIPK3
Synonyms:	RIP3

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	518 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Essential for cellular necroptosis in response to TNF-alpha family of death-inducing cytokines. Upon induction of necrosis, RIPK3 interacts with, and phosphorylates RIPK1 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 By similarity. Ref.9 Ref.10 Ref.11
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	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. Binds TRAF2 is recruited to the TNFR-1 signaling complex. Interacts with PYGL, GLUL and GLUD1; these interactions result in activation of these metabolic enzymes. Ref.1 Ref.8 Ref.9 Ref.10
Subcellular location	Cytoplasm By similarity. Cell membrane By similarity. Mitochondrion Potential.
Tissue specificity	Highly expressed in the pancreas. Detected at lower levels in heart, placenta, lung and kidney. Isoform 3 is significantly increased in colon and lung cancers. Ref.3
Post-translational modification	RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylation of Ser-199 plays a role in the necroptotic function of RIPK3.
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane Mitochondrion
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	induction of apoptosis by extracellular signals Traceable author statement. Source: ProtInc
Cellular component	mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction Ref.10. Source: IntAct transcription coactivator activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BIRC2	Q13490	3	EBI-298250,EBI-514538
BIRC3	Q13489	3	EBI-298250,EBI-517709
RIPK1	Q13546	7	EBI-298250,EBI-358507

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9Y572-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9Y572-2)

Also known as: Beta;

The sequence of this isoform differs from the canonical sequence as follows:
     220-518: VELPTEPSLV...PQGWYNHSGK → CQPNHHSCTKQCATGRTGLHWLSCPKPGLRLPA

Isoform 3 (identifier: Q9Y572-3)

Also known as: Gamma;

The sequence of this isoform differs from the canonical sequence as follows:
     222-518: LPTEPSLVYE...PQGWYNHSGK → CKTLGGFWDP

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 518	518	Receptor-interacting serine/threonine-protein kinase 3		PRO_0000086610
Regions
	Domain	21 – 287	267	Protein kinase
	Nucleotide binding	27 – 35	9	ATP By similarity
	Motif	450 – 466	17	RIP homotypic interaction motif (RHIM)
Sites
	Active site	142	1	Proton acceptor By similarity
	Binding site	50	1	ATP
Amino acid modifications
	Modified residue	199	1	Phosphoserine; by autocatalysis Ref.8 Ref.10
Natural variations
	Alternative sequence	220 – 518	299	VELPT…NHSGK → CQPNHHSCTKQCATGRTGLH WLSCPKPGLRLPA in isoform 2.		VSP_035106
	Alternative sequence	222 – 518	297	LPTEP…NHSGK → CKTLGGFWDP in isoform 3.		VSP_035107
	Natural variant	260	1	E → V. Corresponds to variant rs7153640 [ dbSNP | Ensembl ].		VAR_051664
	Natural variant	300	1	T → M. Ref.13 Corresponds to variant rs34106261 [ dbSNP | Ensembl ].		VAR_041048
	Natural variant	492	1	P → Q. Ref.13 Corresponds to variant rs3212254 [ dbSNP | Ensembl ].		VAR_041049
Experimental info
	Mutagenesis	50	1	K → A: Abolishes kinase activity. Ref.1 Ref.2
	Mutagenesis	50	1	K → D: Abolishes kinase activity. Ref.1 Ref.2
	Sequence conflict	30	1	G → D in AAD39005. Ref.1
	Sequence conflict	150	1	L → P in AAD39005. Ref.1
	Sequence conflict	309	1	R → K in AAD39005. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified September 2, 2008. Version 2. Checksum: BF755F8A0B1810A1	FASTA	518	56,887
	10 20 30 40 50 60 MSCVKLWPSG APAPLVSIEE LENQELVGKG GFGTVFRAQH RKWGYDVAVK IVNSKAISRE 70 80 90 100 110 120 VKAMASLDNE FVLRLEGVIE KVNWDQDPKP ALVTKFMENG SLSGLLQSQC PRPWPLLCRL 130 140 150 160 170 180 LKEVVLGMFY LHDQNPVLLH RDLKPSNVLL DPELHVKLAD FGLSTFQGGS QSGTGSGEPG 190 200 210 220 230 240 GTLGYLAPEL FVNVNRKAST ASDVYSFGIL MWAVLAGREV ELPTEPSLVY EAVCNRQNRP 250 260 270 280 290 300 SLAELPQAGP ETPGLEGLKE LMQLCWSSEP KDRPSFQECL PKTDEVFQMV ENNMNAAVST 310 320 330 340 350 360 VKDFLSQLRS SNRRFSIPES GQGGTEMDGF RRTIENQHSR NDVMVSEWLN KLNLEEPPSS 370 380 390 400 410 420 VPKKCPSLTK RSRAQEEQVP QAWTAGTSSD SMAQPPQTPE TSTFRNQMPS PTSTGTPSPG 430 440 450 460 470 480 PRGNQGAERQ GMNWSCRTPE PNPVTGRPLV NIYNCSGVQV GDNNYLTMQQ TTALPTWGLA 490 500 510 PSGKGRGLQH PPPVGSQEGP KDPEAWSRPQ GWYNHSGK
	Isoform 2 (Beta) [UniParc]. Checksum: 20D7DFAB11AEECEF	FASTA	252	27,574
	10 20 30 40 50 60 MSCVKLWPSG APAPLVSIEE LENQELVGKG GFGTVFRAQH RKWGYDVAVK IVNSKAISRE 70 80 90 100 110 120 VKAMASLDNE FVLRLEGVIE KVNWDQDPKP ALVTKFMENG SLSGLLQSQC PRPWPLLCRL 130 140 150 160 170 180 LKEVVLGMFY LHDQNPVLLH RDLKPSNVLL DPELHVKLAD FGLSTFQGGS QSGTGSGEPG 190 200 210 220 230 240 GTLGYLAPEL FVNVNRKAST ASDVYSFGIL MWAVLAGREC QPNHHSCTKQ CATGRTGLHW 250 LSCPKPGLRL PA
	Isoform 3 (Gamma) [UniParc]. Checksum: 8E6E045EC3B11DEF	FASTA	231	25,326
	10 20 30 40 50 60 MSCVKLWPSG APAPLVSIEE LENQELVGKG GFGTVFRAQH RKWGYDVAVK IVNSKAISRE 70 80 90 100 110 120 VKAMASLDNE FVLRLEGVIE KVNWDQDPKP ALVTKFMENG SLSGLLQSQC PRPWPLLCRL 130 140 150 160 170 180 LKEVVLGMFY LHDQNPVLLH RDLKPSNVLL DPELHVKLAD FGLSTFQGGS QSGTGSGEPG 190 200 210 220 230 GTLGYLAPEL FVNVNRKAST ASDVYSFGIL MWAVLAGREV ECKTLGGFWD P

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB." Yu P.W., Huang B.C.B., Shen M., Quast J., Chan E., Xu X., Nolan G.P., Payan D.G., Luo Y. Curr. Biol. 9:539-542(1999) [PubMed: 10339433] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF LYS-50, INTERACTION WITH RIPK1. Tissue: Cervix carcinoma and Lymphocyte.
[2]	"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: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF LYS-50. Tissue: Aortic endothelium and Fetal brain.
[3]	"RIP3 beta and RIP3 gamma, two novel splice variants of receptor-interacting protein 3 (RIP3), downregulate RIP3-induced apoptosis." Yang Y., Hu W., Feng S., Ma J., Wu M. Biochem. Biophys. Res. Commun. 332:181-187(2005) [PubMed: 15896315] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), TISSUE SPECIFICITY.
[4]	"The DNA sequence and analysis of human chromosome 14." Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., Du H. , Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., Waterston R., Hood L., Weissenbach J. Nature 421:601-607(2003) [PubMed: 12508121] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). Tissue: Thalamus.
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"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] (ISOFORM 1). Tissue: Blood.
[8]	"Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3." Sun X., Yin J., Starovasnik M.A., Fairbrother W.J., Dixit V.M. J. Biol. Chem. 277:9505-9511(2002) [PubMed: 11734559] [Abstract] Cited for: RIP HOMOTYPIC INTERACTION MOTIF, PHOSPHORYLATION AT SER-199, INTERACTION WITH RIPK1.
[9]	"RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis." Zhang D.W., Shao J., Lin J., Zhang N., Lu B.J., Lin S.C., Dong M.Q., Han J. Science 325:332-336(2009) [PubMed: 19498109] [Abstract] Cited for: FUNCTION, INTERACTION WITH PYGL; GLUL AND GLUD1.
[10]	"Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha." He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X. Cell 137:1100-1111(2009) [PubMed: 19524512] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-199, INTERACTION WITH RIPK1.
[11]	"Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation." Cho Y.S., Challa S., Moquin D., Genga R., Ray T.D., Guildford M., Chan F.K. Cell 137:1112-1123(2009) [PubMed: 19524513] [Abstract] Cited for: FUNCTION.
[12]	"The role of the kinases RIP1 and RIP3 in TNF-induced necrosis." Vandenabeele P., Declercq W., Van Herreweghe F., Vanden Berghe T. Sci. Signal. 3:RE4-RE4(2010) [PubMed: 20354226] [Abstract] Cited for: REVIEW.
[13]	"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] MET-300 AND GLN-492.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF156884 mRNA. Translation: AAD39005.1. AY453693 mRNA. Translation: AAS16359.1. AY494982 mRNA. Translation: AAS75516.1. AY494983 mRNA. Translation: AAS75517.1. AL096870 Genomic DNA. No translation available. AK296140 mRNA. Translation: BAG58881.1. CH471078 Genomic DNA. Translation: EAW66021.1. BC062584 mRNA. Translation: AAH62584.1.
IPI	IPI00847572. IPI00896383. IPI00940090.
RefSeq	NP_006862.2. NM_006871.3.
UniGene	Hs.268551.
3D structure databases
ProteinModelPortal	Q9Y572.
SMR	Q9Y572. Positions 14-287.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9Y572. 7 interactions.
MINT	MINT-1131399.
STRING	Q9Y572.
Polymorphism databases
DMDM	205371831.
Proteomic databases
PRIDE	Q9Y572.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000216274; ENSP00000216274; ENSG00000129465.
GeneID	11035.
KEGG	hsa:11035.
Organism-specific databases
CTD	11035.
GeneCards	GC14M024811.
H-InvDB	HIX0202097.
HGNC	HGNC:10021. RIPK3.
MIM	605817. gene.
neXtProt	NX_Q9Y572.
PharmGKB	PA34396.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG06469.
GeneTree	ENSGT00550000074536.
HOGENOM	HBG125345.
HOVERGEN	HBG062538.
InParanoid	Q9Y572.
OMA	RFMENGS.
OrthoDB	EOG40CHHC.
PhylomeDB	Q9Y572.
Enzyme and pathway databases
BRENDA	2.7.10.2. 2681.
Gene expression databases
ArrayExpress	Q9Y572.
Bgee	Q9Y572.
CleanEx	HS_RIPK3.
Genevestigator	Q9Y572.
GermOnline	ENSG00000129465. Homo sapiens.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_kinase-like_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
KO	K08847.
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
SOURCE	Search...

Entry information

Entry name

RIPK3_HUMAN

Accession

Primary (citable) accession number: Q9Y572
Secondary accession number(s): B4DJL9 , C4AM87, Q5J795, Q5J796, Q6P5Y1

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 2, 2002
Last sequence update:	September 2, 2008
Last modified:	January 25, 2012
This is version 112 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.