ID RIPK3_HUMAN Reviewed; 518 AA. AC Q9Y572; B4DJL9; C4AM87; Q5J795; Q5J796; Q6P5Y1; DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot. DT 02-SEP-2008, sequence version 2. DT 27-MAR-2024, entry version 213. DE RecName: Full=Receptor-interacting serine/threonine-protein kinase 3 {ECO:0000305}; DE EC=2.7.11.1 {ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:22265413}; DE AltName: Full=RIP-like protein kinase 3 {ECO:0000303|PubMed:10339433}; DE AltName: Full=Receptor-interacting protein 3 {ECO:0000303|PubMed:10339433}; DE Short=RIP-3 {ECO:0000303|PubMed:10339433}; GN Name=RIPK3 {ECO:0000312|HGNC:HGNC:10021}; GN Synonyms=RIP3 {ECO:0000303|PubMed:10339433}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF LYS-50, AND RP INTERACTION WITH RIPK1. RC TISSUE=Cervix carcinoma, and Lymphocyte; RX PubMed=10339433; DOI=10.1016/s0960-9822(99)80239-5; RA Yu P.W., Huang B.C.B., Shen M., Quast J., Chan E., Xu X., Nolan G.P., RA Payan D.G., Luo Y.; RT "Identification of RIP3, a RIP-like kinase that activates apoptosis and RT NFkappaB."; RL Curr. Biol. 9:539-542(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND MUTAGENESIS OF LYS-50. RC TISSUE=Aortic endothelium, and Fetal brain; RX PubMed=10358032; DOI=10.1074/jbc.274.24.16871; RA Sun X., Lee J., Navas T., Baldwin D.T., Stewart T.A., Dixit V.M.; RT "RIP3, a novel apoptosis-inducing kinase."; RL J. Biol. Chem. 274:16871-16875(1999). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), AND TISSUE SPECIFICITY. RX PubMed=15896315; DOI=10.1016/j.bbrc.2005.04.114; RA Yang Y., Hu W., Feng S., Ma J., Wu M.; RT "RIP3 beta and RIP3 gamma, two novel splice variants of receptor- RT interacting protein 3 (RIP3), downregulate RIP3-induced apoptosis."; RL Biochem. Biophys. Res. Commun. 332:181-187(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Thalamus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Blood; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP RIP HOMOTYPIC INTERACTION MOTIF, PHOSPHORYLATION AT SER-199, AND RP INTERACTION WITH RIPK1. RX PubMed=11734559; DOI=10.1074/jbc.m109488200; RA Sun X., Yin J., Starovasnik M.A., Fairbrother W.J., Dixit V.M.; RT "Identification of a novel homotypic interaction motif required for the RT phosphorylation of receptor-interacting protein (RIP) by RIP3."; RL J. Biol. Chem. 277:9505-9511(2002). RN [9] RP FUNCTION, AND INTERACTION WITH PYGL; GLUL AND GLUD1. RX PubMed=19498109; DOI=10.1126/science.1172308; RA Zhang D.W., Shao J., Lin J., Zhang N., Lu B.J., Lin S.C., Dong M.Q., RA Han J.; RT "RIP3, an energy metabolism regulator that switches TNF-induced cell death RT from apoptosis to necrosis."; RL Science 325:332-336(2009). RN [10] RP FUNCTION, PHOSPHORYLATION AT SER-199, AND INTERACTION WITH RIPK1. RX PubMed=19524512; DOI=10.1016/j.cell.2009.05.021; RA He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X.; RT "Receptor interacting protein kinase-3 determines cellular necrotic RT response to TNF-alpha."; RL Cell 137:1100-1111(2009). RN [11] RP FUNCTION, AND PHOSPHORYLATION. RX PubMed=19524513; DOI=10.1016/j.cell.2009.05.037; RA Cho Y.S., Challa S., Moquin D., Genga R., Ray T.D., Guildford M., RA Chan F.K.; RT "Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates RT programmed necrosis and virus-induced inflammation."; RL Cell 137:1112-1123(2009). RN [12] RP REVIEW. RX PubMed=20354226; DOI=10.1126/scisignal.3115re4; RA Vandenabeele P., Declercq W., Van Herreweghe F., Vanden Berghe T.; RT "The role of the kinases RIP1 and RIP3 in TNF-induced necrosis."; RL Sci. Signal. 3:RE4-RE4(2010). RN [13] RP UBIQUITINATION BY BIRC2/C-IAP1 AND BIRC3/C-IAP2, AND INTERACTION WITH RP BIRC2/C-IAP1; BIRC3/C-IAP2 AND XIAP/BIRC4. RX PubMed=21931591; DOI=10.1371/journal.pone.0022356; RA Bertrand M.J., Lippens S., Staes A., Gilbert B., Roelandt R., De Medts J., RA Gevaert K., Declercq W., Vandenabeele P.; RT "cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin RT chains to receptor interacting proteins kinases 1 to 4 (RIP1-4)."; RL PLoS ONE 6:E22356-E22356(2011). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH MLKL, PHOSPHORYLATION AT RP SER-227, ACTIVE SITE, AND MUTAGENESIS OF ASP-142 AND SER-227. RX PubMed=22265413; DOI=10.1016/j.cell.2011.11.031; RA Sun L., Wang H., Wang Z., He S., Chen S., Liao D., Wang L., Yan J., Liu W., RA Lei X., Wang X.; RT "Mixed lineage kinase domain-like protein mediates necrosis signaling RT downstream of RIP3 kinase."; RL Cell 148:213-227(2012). RN [15] RP FUNCTION, IDENTIFICATION IN COMPLEX WITH PGAM5; RIPK1 AND MLKL, AND RP MUTAGENESIS OF LYS-50. RX PubMed=22265414; DOI=10.1016/j.cell.2011.11.030; RA Wang Z., Jiang H., Chen S., Du F., Wang X.; RT "The mitochondrial phosphatase PGAM5 functions at the convergence point of RT multiple necrotic death pathways."; RL Cell 148:228-243(2012). RN [16] RP INTERACTION WITH ARHGEF2. RX PubMed=21887730; DOI=10.1002/ibd.21851; RA Zhao Y., Alonso C., Ballester I., Song J.H., Chang S.Y., Guleng B., RA Arihiro S., Murray P.J., Xavier R., Kobayashi K.S., Reinecker H.C.; RT "Control of NOD2 and Rip2-dependent innate immune activation by GEF-H1."; RL Inflamm. Bowel Dis. 18:603-612(2012). RN [17] RP FUNCTION, AND INTERACTION WITH MLKL. RX PubMed=22421439; DOI=10.1073/pnas.1200012109; RA Zhao J., Jitkaew S., Cai Z., Choksi S., Li Q., Luo J., Liu Z.G.; RT "Mixed lineage kinase domain-like is a key receptor interacting protein 3 RT downstream component of TNF-induced necrosis."; RL Proc. Natl. Acad. Sci. U.S.A. 109:5322-5327(2012). RN [18] RP FUNCTION, AND INTERACTION WITH HUMAN HERPESVIRUS PROTEIN 1 RIR1 (MICROBIAL RP INFECTION). RX PubMed=25316792; DOI=10.1073/pnas.1412767111; RA Wang X., Li Y., Liu S., Yu X., Li L., Shi C., He W., Li J., Xu L., Hu Z., RA Yu L., Yang Z., Chen Q., Ge L., Zhang Z., Zhou B., Jiang X., Chen S., RA He S.; RT "Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus RT 1 (HSV-1) protein ICP6 triggers host antiviral defense."; RL Proc. Natl. Acad. Sci. U.S.A. 111:15438-15443(2014). RN [19] RP INTERACTION WITH HERPES SIMPLEX VIRUS 1 AND 2 PROTEIN RIR1 (MICROBIAL RP INFECTION). RX PubMed=25674983; DOI=10.1016/j.chom.2015.01.003; RA Guo H., Omoto S., Harris P.A., Finger J.N., Bertin J., Gough P.J., RA Kaiser W.J., Mocarski E.S.; RT "Herpes simplex virus suppresses necroptosis in human cells."; RL Cell Host Microbe 17:243-251(2015). RN [20] RP FUNCTION, UBIQUITINATION AT LYS-363, PROTEASOMAL DEGRADATION, MUTAGENESIS RP OF LYS-50; THR-182; TYR-185; SER-227 AND LYS-363, INTERACTION WITH PELI1; RP STUB1; RIPK1; TRAF2; MLKL AND BUB1B, AND PHOSPHORYLATION AT THR-182 AND RP SER-227. RX PubMed=29883609; DOI=10.1016/j.molcel.2018.05.016; RA Choi S.W., Park H.H., Kim S., Chung J.M., Noh H.J., Kim S.K., Song H.K., RA Lee C.W., Morgan M.J., Kang H.C., Kim Y.S.; RT "PELI1 selectively targets kinase-active RIP3 for ubiquitylation-dependent RT proteasomal degradation."; RL Mol. Cell 70:920-935(2018). RN [21] RP FUNCTION, AND INTERACTION WITH CASP6. RX PubMed=32298652; DOI=10.1016/j.cell.2020.03.040; RA Zheng M., Karki R., Vogel P., Kanneganti T.D.; RT "Caspase-6 is a key regulator of innate immunity, inflammasome activation, RT and host defense."; RL Cell 181:674-687(2020). RN [22] RP FUNCTION, PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION), AND MUTAGENESIS OF RP 458-VAL--GLY-461. RX PubMed=32657447; DOI=10.15252/embj.2020104469; RA Ashida H., Sasakawa C., Suzuki T.; RT "A unique bacterial tactic to circumvent the cell death crosstalk induced RT by blockade of caspase-8."; RL EMBO J. 39:e104469-e104469(2020). RN [23] RP FUNCTION (MICROBIAL INFECTION), INTERACTION WITH HHV-1 PROTEIN RIR1 RP (MICROBIAL INFECTION), AND DOMAIN (MICROBIAL INFECTION). RX PubMed=33348174; DOI=10.1016/j.bpc.2020.106524; RA Shanmugam N., Baker M.O.D.G., Sanz-Hernandez M., Sierecki E., Gambin Y., RA Steain M., Pham C.L.L., Sunde M.; RT "Herpes simplex virus encoded ICP6 protein forms functional amyloid RT assemblies with necroptosis-associated host proteins."; RL Biophys. Chem. 269:106524-106524(2021). RN [24] RP VARIANTS [LARGE SCALE ANALYSIS] MET-300 AND GLN-492. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [25] {ECO:0007744|PDB:5V7Z, ECO:0007744|PDB:5ZCK} RP STRUCTURE BY NMR OF 448-462 IN COMPLEX WITH RIPK1, X-RAY CRYSTALLOGRAPHY RP (1.27 ANGSTROMS) OF 458-461 IN COMPLEX WITH RIPK1, INTERACTION WITH RIPK1, RP AND DOMAIN. RX PubMed=29681455; DOI=10.1016/j.cell.2018.03.032; RA Mompean M., Li W., Li J., Laage S., Siemer A.B., Bozkurt G., Wu H., RA McDermott A.E.; RT "The structure of the necrosome RIPK1-RIPK3 core, a human hetero-amyloid RT signaling complex."; RL Cell 173:1244-1253(2018). CC -!- FUNCTION: Serine/threonine-protein kinase that activates necroptosis CC and apoptosis, two parallel forms of cell death (PubMed:19524512, CC PubMed:19524513, PubMed:22265413, PubMed:22265414, PubMed:22421439, CC PubMed:29883609, PubMed:32657447). Necroptosis, a programmed cell death CC process in response to death-inducing TNF-alpha family members, is CC triggered by RIPK3 following activation by ZBP1 (PubMed:19524512, CC PubMed:19524513, PubMed:22265413, PubMed:22265414, PubMed:22421439, CC PubMed:29883609, PubMed:32298652). Activated RIPK3 forms a necrosis- CC inducing complex and mediates phosphorylation of MLKL, promoting MLKL CC localization to the plasma membrane and execution of programmed CC necrosis characterized by calcium influx and plasma membrane damage CC (PubMed:19524512, PubMed:19524513, PubMed:22265413, PubMed:22265414, CC PubMed:22421439, PubMed:25316792, PubMed:29883609). In addition to TNF- CC induced necroptosis, necroptosis can also take place in the nucleus in CC response to orthomyxoviruses infection: following ZBP1 activation, CC which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes CC phosphorylation and activation of MLKL, promoting disruption of the CC nuclear envelope and leakage of cellular DNA into the cytosol (By CC similarity). Also regulates apoptosis: apoptosis depends on RIPK1, FADD CC and CASP8, and is independent of MLKL and RIPK3 kinase activity (By CC similarity). Phosphorylates RIPK1: RIPK1 and RIPK3 undergo reciprocal CC auto- and trans-phosphorylation (PubMed:19524513). In some cell types, CC also able to restrict viral replication by promoting cell death- CC independent responses (By similarity). In response to Zika virus CC infection in neurons, promotes a cell death-independent pathway that CC restricts viral replication: together with ZBP1, promotes a death- CC independent transcriptional program that modifies the cellular CC metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and CC production of the metabolite itaconate (By similarity). Itaconate CC inhibits the activity of succinate dehydrogenase, generating a CC metabolic state in neurons that suppresses replication of viral genomes CC (By similarity). RIPK3 binds to and enhances the activity of three CC metabolic enzymes: GLUL, GLUD1, and PYGL (PubMed:19498109). These CC metabolic enzymes may eventually stimulate the tricarboxylic acid cycle CC and oxidative phosphorylation, which could result in enhanced ROS CC production (PubMed:19498109). {ECO:0000250|UniProtKB:Q9QZL0, CC ECO:0000269|PubMed:19498109, ECO:0000269|PubMed:19524512, CC ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:22265413, CC ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439, CC ECO:0000269|PubMed:25316792, ECO:0000269|PubMed:29883609, CC ECO:0000269|PubMed:32298652, ECO:0000269|PubMed:32657447}. CC -!- FUNCTION: (Microbial infection) In case of herpes simplex virus 1/HHV-1 CC infection, forms heteromeric amyloid structures with HHV-1 protein CC RIR1/ICP6 which may inhibit RIPK3-mediated necroptosis, thereby CC preventing host cell death pathway and allowing viral evasion. CC {ECO:0000269|PubMed:33348174}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:22265413}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:19524513, CC ECO:0000269|PubMed:22265413}; CC -!- ACTIVITY REGULATION: Activity is stimulated by ZBP1, which senses CC double-stranded Z-RNA structures (By similarity). RIPK3-dependent CC necroptosis is inhibited by RIPK1: RIPK1 prevents the ZBP1-induced CC activation of RIPK3 via FADD-mediated recruitment of CASP8, which CC cleaves RIPK1 and limits TNF-induced necroptosis (By similarity). CC {ECO:0000250|UniProtKB:Q9QZL0}. CC -!- SUBUNIT: Interacts (via RIP homotypic interaction motif) with RIPK1 CC (via RIP homotypic interaction motif); this interaction induces RIPK1 CC phosphorylation and formation of a RIPK1-RIPK3 necrosis-inducing CC complex (PubMed:10339433, PubMed:11734559, PubMed:19524512, CC PubMed:29681455). Interacts with MLKL; the interaction is direct and CC triggers necroptosis (PubMed:22265413, PubMed:22421439). Interacts with CC ZBP1 (via RIP homotypic interaction motif); interaction with ZBP1 CC activates RIPK3, triggering necroptosis (By similarity). Upon TNF- CC induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 CC and MLKL; the formation of this complex leads to PGAM5 phosphorylation CC and increase in PGAM5 phosphatase activity (PubMed:22265413, CC PubMed:22265414, PubMed:22421439). Binds TRAF2 and is recruited to the CC TNFR-1 signaling complex (PubMed:29883609). Interacts with PYGL, GLUL CC and GLUD1; these interactions result in activation of these metabolic CC enzymes (PubMed:19498109). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 CC and XIAP/BIRC4 (PubMed:21931591). Interacts with ARHGEF2 CC (PubMed:21887730). Interacts with PELI1 (via atypical FHA domain); the CC phosphorylated form at Thr-182 binds preferentially to PELI1 CC (PubMed:29883609). Interacts with BUB1B, TRAF2 and STUB1 CC (PubMed:29883609). Interacts with CASP6 (PubMed:32298652). Component of CC the AIM2 PANoptosome complex, a multiprotein complex that drives CC inflammatory cell death (PANoptosis) (By similarity). CC {ECO:0000250|UniProtKB:Q9QZL0, ECO:0000269|PubMed:10339433, CC ECO:0000269|PubMed:11734559, ECO:0000269|PubMed:19498109, CC ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:21887730, CC ECO:0000269|PubMed:21931591, ECO:0000269|PubMed:22265413, CC ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439, CC ECO:0000269|PubMed:29681455, ECO:0000269|PubMed:29883609, CC ECO:0000269|PubMed:32298652}. CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction CC motif/RHIM) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via CC RHIM); this interaction may induce heteromeric amyloid assemblies and CC prevent necroptosis activation. {ECO:0000269|PubMed:25674983, CC ECO:0000269|PubMed:33348174, ECO:0000305|PubMed:25316792}. CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction CC motif/RHIM) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via CC RHIM); this interaction prevents necroptosis activation. CC {ECO:0000269|PubMed:25674983}. CC -!- INTERACTION: CC Q9Y572; Q13490: BIRC2; NbExp=3; IntAct=EBI-298250, EBI-514538; CC Q9Y572; Q13489: BIRC3; NbExp=3; IntAct=EBI-298250, EBI-517709; CC Q9Y572; Q8NB16: MLKL; NbExp=10; IntAct=EBI-298250, EBI-1055040; CC Q9Y572; Q13546: RIPK1; NbExp=26; IntAct=EBI-298250, EBI-358507; CC Q9Y572; Q9Y572: RIPK3; NbExp=5; IntAct=EBI-298250, EBI-298250; CC Q9Y572; Q9H171: ZBP1; NbExp=4; IntAct=EBI-298250, EBI-6264672; CC Q9Y572; J9TC74: ORF3a; Xeno; NbExp=3; IntAct=EBI-298250, EBI-25488975; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:22265413}. CC Nucleus {ECO:0000250|UniProtKB:Q9QZL0}. Note=Mainly cytoplasmic. CC Present in the nucleus in response to influenza A virus (IAV) CC infection. {ECO:0000250|UniProtKB:Q9QZL0}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9Y572-1; Sequence=Displayed; CC Name=2; Synonyms=Beta; CC IsoId=Q9Y572-2; Sequence=VSP_035106; CC Name=3; Synonyms=Gamma; CC IsoId=Q9Y572-3; Sequence=VSP_035107; CC -!- TISSUE SPECIFICITY: Highly expressed in the pancreas. Detected at lower CC levels in heart, placenta, lung and kidney. CC {ECO:0000269|PubMed:15896315}. CC -!- TISSUE SPECIFICITY: [Isoform 3]: Expression is significantly increased CC in colon and lung cancers. {ECO:0000269|PubMed:15896315}. CC -!- DOMAIN: The RIP homotypic interaction motif/RHIM mediates interaction CC with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid CC serpentine fold, stabilized by hydrophobic packing and featuring an CC unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from CC RIPK3). {ECO:0000269|PubMed:29681455}. CC -!- DOMAIN: (Microbial infection) The RIP homotypic interaction motif/RHIM CC mediates interaction with the RHIM motif of the herpes simplex virus CC 1/HHV-1 protein RIR1/ICP6 to form heteromeric amyloid structures. CC {ECO:0000269|PubMed:33348174}. CC -!- PTM: (Microbial infection) Proteolytically cleaved by S.flexneri OspD3 CC within the RIP homotypic interaction motif (RHIM), leading to its CC degradation and inhibition of necroptosis. CC {ECO:0000269|PubMed:32657447}. CC -!- PTM: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation CC (PubMed:19524513). Autophosphorylated following interaction with ZBP1 CC (By similarity). Phosphorylation of Ser-199 plays a role in the CC necroptotic function of RIPK3 (PubMed:11734559, PubMed:19524512). CC Autophosphorylates at Ser-227 following activation by ZBP1: CC phosphorylation at these sites is a hallmark of necroptosis and is CC required for binding MLKL (PubMed:22265413). Phosphorylation at Thr-182 CC is important for its kinase activity, interaction with PELI1 and PELI1- CC mediated 'Lys-48'-linked polyubiquitination and for its ability to CC mediate TNF-induced necroptosis (PubMed:29883609). CC {ECO:0000250|UniProtKB:Q9QZL0, ECO:0000269|PubMed:11734559, CC ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:19524513, CC ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:29883609}. CC -!- PTM: Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by CC BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B CC (PubMed:21931591). Polyubiquitinated with 'Lys-48'-linked chains by CC PELI1 leading to its subsequent proteasome-dependent degradation. CC Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent CC degradation (PubMed:29883609). {ECO:0000269|PubMed:21931591, CC ECO:0000269|PubMed:29883609}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF156884; AAD39005.1; -; mRNA. DR EMBL; AY453693; AAS16359.1; -; mRNA. DR EMBL; AY494982; AAS75516.1; -; mRNA. DR EMBL; AY494983; AAS75517.1; -; mRNA. DR EMBL; AL096870; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AK296140; BAG58881.1; -; mRNA. DR EMBL; CH471078; EAW66021.1; -; Genomic_DNA. DR EMBL; BC062584; AAH62584.1; -; mRNA. DR CCDS; CCDS9628.1; -. [Q9Y572-1] DR RefSeq; NP_006862.2; NM_006871.3. [Q9Y572-1] DR PDB; 5V7Z; NMR; -; A/C/E/G=448-462. DR PDB; 5ZCK; X-ray; 1.27 A; A=458-461. DR PDB; 7DA4; EM; 4.24 A; A/B/C=388-518. DR PDB; 7DAC; NMR; -; A/B/C/D/E=418-518. DR PDB; 7MON; X-ray; 2.23 A; B=1-316. DR PDB; 7MX3; X-ray; 3.23 A; A/B/C/D=2-315. DR PDBsum; 5V7Z; -. DR PDBsum; 5ZCK; -. DR PDBsum; 7DA4; -. DR PDBsum; 7DAC; -. DR PDBsum; 7MON; -. DR PDBsum; 7MX3; -. DR AlphaFoldDB; Q9Y572; -. DR EMDB; EMD-30622; -. DR SMR; Q9Y572; -. DR BioGRID; 116224; 66. DR DIP; DIP-27519N; -. DR IntAct; Q9Y572; 16. DR MINT; Q9Y572; -. DR STRING; 9606.ENSP00000216274; -. DR BindingDB; Q9Y572; -. DR ChEMBL; CHEMBL1795199; -. DR GuidetoPHARMACOLOGY; 2191; -. DR TCDB; 8.A.23.1.52; the basigin (basigin) family. DR GlyCosmos; Q9Y572; 1 site, 1 glycan. DR GlyGen; Q9Y572; 14 sites, 1 O-linked glycan (14 sites). DR iPTMnet; Q9Y572; -. DR PhosphoSitePlus; Q9Y572; -. DR BioMuta; RIPK3; -. DR DMDM; 205371831; -. DR CPTAC; CPTAC-903; -. DR CPTAC; CPTAC-904; -. DR jPOST; Q9Y572; -. DR MassIVE; Q9Y572; -. DR MaxQB; Q9Y572; -. DR PaxDb; 9606-ENSP00000216274; -. DR PeptideAtlas; Q9Y572; -. DR ProteomicsDB; 86299; -. [Q9Y572-1] DR ProteomicsDB; 86300; -. [Q9Y572-2] DR ProteomicsDB; 86301; -. [Q9Y572-3] DR ABCD; Q9Y572; 2 sequenced antibodies. DR Antibodypedia; 9228; 1036 antibodies from 46 providers. DR DNASU; 11035; -. DR Ensembl; ENST00000216274.10; ENSP00000216274.5; ENSG00000129465.16. [Q9Y572-1] DR Ensembl; ENST00000554756.1; ENSP00000452328.1; ENSG00000129465.16. [Q9Y572-3] DR Ensembl; ENST00000643393.1; ENSP00000495915.1; ENSG00000285379.2. [Q9Y572-3] DR Ensembl; ENST00000646516.2; ENSP00000495490.1; ENSG00000285379.2. [Q9Y572-1] DR GeneID; 11035; -. DR KEGG; hsa:11035; -. DR MANE-Select; ENST00000216274.10; ENSP00000216274.5; NM_006871.4; NP_006862.2. DR UCSC; uc001wpb.4; human. [Q9Y572-1] DR AGR; HGNC:10021; -. DR CTD; 11035; -. DR DisGeNET; 11035; -. DR GeneCards; RIPK3; -. DR HGNC; HGNC:10021; RIPK3. DR HPA; ENSG00000129465; Low tissue specificity. DR MIM; 605817; gene. DR neXtProt; NX_Q9Y572; -. DR OpenTargets; ENSG00000129465; -. DR PharmGKB; PA34396; -. DR VEuPathDB; HostDB:ENSG00000129465; -. DR eggNOG; KOG0192; Eukaryota. DR GeneTree; ENSGT00940000160206; -. DR HOGENOM; CLU_559689_0_0_1; -. DR InParanoid; Q9Y572; -. DR OMA; WDYVSGP; -. DR OrthoDB; 2968576at2759; -. DR PhylomeDB; Q9Y572; -. DR TreeFam; TF106506; -. DR BRENDA; 2.7.10.2; 2681. DR PathwayCommons; Q9Y572; -. DR Reactome; R-HSA-168927; TICAM1, RIP1-mediated IKK complex recruitment. DR Reactome; R-HSA-1810476; RIP-mediated NFkB activation via ZBP1. DR Reactome; R-HSA-2562578; TRIF-mediated programmed cell death. DR Reactome; R-HSA-3295583; TRP channels. DR Reactome; R-HSA-5213460; RIPK1-mediated regulated necrosis. DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death. DR Reactome; R-HSA-9013957; TLR3-mediated TICAM1-dependent programmed cell death. DR Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1. DR Reactome; R-HSA-9686347; Microbial modulation of RIPK1-mediated regulated necrosis. DR Reactome; R-HSA-9692913; SARS-CoV-1-mediated effects on programmed cell death. DR Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses. DR SignaLink; Q9Y572; -. DR SIGNOR; Q9Y572; -. DR BioGRID-ORCS; 11035; 35 hits in 1194 CRISPR screens. DR ChiTaRS; RIPK3; human. DR GeneWiki; RIPK3; -. DR GenomeRNAi; 11035; -. DR Pharos; Q9Y572; Tchem. DR PRO; PR:Q9Y572; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q9Y572; Protein. DR Bgee; ENSG00000129465; Expressed in granulocyte and 93 other cell types or tissues. DR ExpressionAtlas; Q9Y572; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProt. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProt. DR GO; GO:0044877; F:protein-containing complex binding; IMP:UniProtKB. DR GO; GO:0003713; F:transcription coactivator activity; TAS:ProtInc. DR GO; GO:0032147; P:activation of protein kinase activity; IMP:UniProtKB. DR GO; GO:1990000; P:amyloid fibril formation; IMP:UniProtKB. DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:ProtInc. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISS:ARUK-UCL. DR GO; GO:0051607; P:defense response to virus; ISS:UniProtKB. DR GO; GO:0097528; P:execution phase of necroptosis; ISS:UniProtKB. DR GO; GO:0048535; P:lymph node development; ISS:UniProtKB. DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB. DR GO; GO:0097527; P:necroptotic signaling pathway; IDA:UniProt. DR GO; GO:0038061; P:non-canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0060545; P:positive regulation of necroptotic process; IDA:UniProtKB. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB. DR GO; GO:0010922; P:positive regulation of phosphatase activity; IMP:UniProtKB. DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IEA:Ensembl. DR GO; GO:0097300; P:programmed necrotic cell death; ISS:ARUK-UCL. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0036211; P:protein modification process; TAS:ProtInc. DR GO; GO:0072593; P:reactive oxygen species metabolic process; IEA:Ensembl. DR GO; GO:0046006; P:regulation of activated T cell proliferation; ISS:UniProtKB. DR GO; GO:0070235; P:regulation of activation-induced cell death of T cells; ISS:UniProtKB. DR GO; GO:0002819; P:regulation of adaptive immune response; ISS:UniProtKB. DR GO; GO:0042981; P:regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:2000452; P:regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation; ISS:UniProtKB. DR GO; GO:0001914; P:regulation of T cell mediated cytotoxicity; ISS:UniProtKB. DR GO; GO:0032649; P:regulation of type II interferon production; ISS:UniProtKB. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR GO; GO:0048536; P:spleen development; ISS:UniProtKB. DR GO; GO:0033077; P:T cell differentiation in thymus; ISS:UniProtKB. DR GO; GO:0043029; P:T cell homeostasis; ISS:UniProtKB. DR GO; GO:0048538; P:thymus development; ISS:UniProtKB. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR025735; RHIM_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR23257:SF985; RECEPTOR-INTERACTING SERINE_THREONINE-PROTEIN KINASE 3; 1. DR PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF12721; RHIM; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q9Y572; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; ATP-binding; Cytoplasm; KW Host-virus interaction; Isopeptide bond; Kinase; Necrosis; KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Ubl conjugation. FT CHAIN 1..518 FT /note="Receptor-interacting serine/threonine-protein kinase FT 3" FT /id="PRO_0000086610" FT DOMAIN 21..287 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 355..443 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 476..518 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 450..466 FT /note="RIP homotypic interaction motif (RHIM)" FT /evidence="ECO:0000269|PubMed:29681455" FT COMPBIAS 372..440 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 142 FT /note="Proton acceptor" FT /evidence="ECO:0000305|PubMed:22265413" FT BINDING 27..35 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 50 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305|PubMed:10339433, FT ECO:0000305|PubMed:10358032, ECO:0000305|PubMed:22265414" FT MOD_RES 2 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QZL0" FT MOD_RES 164 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QZL0" FT MOD_RES 182 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:29883609" FT MOD_RES 199 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:11734559, FT ECO:0000269|PubMed:19524512" FT MOD_RES 227 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:22265413, FT ECO:0000269|PubMed:29883609" FT MOD_RES 252 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q9QZL0" FT MOD_RES 299 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QZL0" FT MOD_RES 333 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q9QZL0" FT MOD_RES 389 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QZL0" FT MOD_RES 401 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q9QZL0" FT CROSSLNK 363 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:29883609" FT VAR_SEQ 220..518 FT /note="VELPTEPSLVYEAVCNRQNRPSLAELPQAGPETPGLEGLKELMQLCWSSEPK FT DRPSFQECLPKTDEVFQMVENNMNAAVSTVKDFLSQLRSSNRRFSIPESGQGGTEMDGF FT RRTIENQHSRNDVMVSEWLNKLNLEEPPSSVPKKCPSLTKRSRAQEEQVPQAWTAGTSS FT DSMAQPPQTPETSTFRNQMPSPTSTGTPSPGPRGNQGAERQGMNWSCRTPEPNPVTGRP FT LVNIYNCSGVQVGDNNYLTMQQTTALPTWGLAPSGKGRGLQHPPPVGSQEGPKDPEAWS FT RPQGWYNHSGK -> CQPNHHSCTKQCATGRTGLHWLSCPKPGLRLPA (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:15896315" FT /id="VSP_035106" FT VAR_SEQ 222..518 FT /note="LPTEPSLVYEAVCNRQNRPSLAELPQAGPETPGLEGLKELMQLCWSSEPKDR FT PSFQECLPKTDEVFQMVENNMNAAVSTVKDFLSQLRSSNRRFSIPESGQGGTEMDGFRR FT TIENQHSRNDVMVSEWLNKLNLEEPPSSVPKKCPSLTKRSRAQEEQVPQAWTAGTSSDS FT MAQPPQTPETSTFRNQMPSPTSTGTPSPGPRGNQGAERQGMNWSCRTPEPNPVTGRPLV FT NIYNCSGVQVGDNNYLTMQQTTALPTWGLAPSGKGRGLQHPPPVGSQEGPKDPEAWSRP FT QGWYNHSGK -> CKTLGGFWDP (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15896315" FT /id="VSP_035107" FT VARIANT 260 FT /note="E -> V (in dbSNP:rs7153640)" FT /id="VAR_051664" FT VARIANT 300 FT /note="T -> M (in dbSNP:rs34106261)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041048" FT VARIANT 492 FT /note="P -> Q (in dbSNP:rs3212254)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041049" FT MUTAGEN 50 FT /note="K->A: Abolishes kinase activity. Loss of PGAM5- and FT MLKL-binding. No effect on RIPK1-binding. Loss of FT interaction with PELI1 and PELI1-mediated ubiquitination. FT No loss of STUB1-mediated ubiquitination." FT /evidence="ECO:0000269|PubMed:10339433, FT ECO:0000269|PubMed:10358032, ECO:0000269|PubMed:22265414, FT ECO:0000269|PubMed:29883609" FT MUTAGEN 50 FT /note="K->D: Abolishes kinase activity." FT /evidence="ECO:0000269|PubMed:10339433, FT ECO:0000269|PubMed:10358032, ECO:0000269|PubMed:22265414" FT MUTAGEN 142 FT /note="D->N: Abolishes kinase activity and ability to FT mediate necroptosis." FT /evidence="ECO:0000269|PubMed:22265413" FT MUTAGEN 182 FT /note="T->A: Abolishes kinase activity. Loss of interaction FT with PELI1 and PELI1-mediated ubiquitination. No loss of FT interaction with STUB1 and STUB1-mediated ubiquitination. FT No loss of interaction with RIPK1. Loss of ability to FT mediate TNF-induced necroptosis. Loss of FT autophosphorylation at Ser-227." FT /evidence="ECO:0000269|PubMed:29883609" FT MUTAGEN 182 FT /note="T->S: No loss of interaction with PELI1 and FT PELI1-mediated ubiquitination. No loss of interaction with FT RIPK1 and MLKL." FT /evidence="ECO:0000269|PubMed:29883609" FT MUTAGEN 185 FT /note="Y->A,F: Loss of interaction with PELI1 and FT PELI1-mediated ubiquitination." FT /evidence="ECO:0000269|PubMed:29883609" FT MUTAGEN 227 FT /note="S->A: Abolishes ability to mediate necroptosis. FT Partial loss of kinase activity. No loss of PELI1-mediated FT degradation." FT /evidence="ECO:0000269|PubMed:22265413, FT ECO:0000269|PubMed:29883609" FT MUTAGEN 227 FT /note="S->D: No loss of PELI1-mediated degradation." FT /evidence="ECO:0000269|PubMed:29883609" FT MUTAGEN 363 FT /note="K->R: Loss of PELI1-mediated ubiquitination. No loss FT of interaction with PELI1." FT /evidence="ECO:0000269|PubMed:29883609" FT MUTAGEN 458..461 FT /note="VQVG->AAAA: Abolished cleavage by S.flexneri OspD3." FT /evidence="ECO:0000269|PubMed:32657447" FT CONFLICT 30 FT /note="G -> D (in Ref. 1; AAD39005)" FT /evidence="ECO:0000305" FT CONFLICT 150 FT /note="L -> P (in Ref. 1; AAD39005)" FT /evidence="ECO:0000305" FT CONFLICT 309 FT /note="R -> K (in Ref. 1; AAD39005)" FT /evidence="ECO:0000305" FT HELIX 18..20 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 21..26 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 35..40 FT /evidence="ECO:0007829|PDB:7MON" FT TURN 41..43 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 45..51 FT /evidence="ECO:0007829|PDB:7MON" FT TURN 54..56 FT /evidence="ECO:0007829|PDB:7MX3" FT HELIX 57..65 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 75..80 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 84..87 FT /evidence="ECO:0007829|PDB:7MX3" FT STRAND 91..95 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 102..107 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 114..133 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 145..147 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 148..150 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 156..158 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 161..163 FT /evidence="ECO:0007829|PDB:7MX3" FT STRAND 165..169 FT /evidence="ECO:0007829|PDB:7MX3" FT HELIX 182..185 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 188..190 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 193..195 FT /evidence="ECO:0007829|PDB:7MX3" FT HELIX 200..216 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 226..233 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 242..244 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 249..252 FT /evidence="ECO:0007829|PDB:7MX3" FT HELIX 255..265 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 270..272 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 276..290 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 291..293 FT /evidence="ECO:0007829|PDB:7MON" FT HELIX 294..309 FT /evidence="ECO:0007829|PDB:7MON" FT STRAND 450..461 FT /evidence="ECO:0007829|PDB:5V7Z" FT STRAND 466..472 FT /evidence="ECO:0007829|PDB:7DAC" SQ SEQUENCE 518 AA; 56887 MW; BF755F8A0B1810A1 CRC64; MSCVKLWPSG APAPLVSIEE LENQELVGKG GFGTVFRAQH RKWGYDVAVK IVNSKAISRE VKAMASLDNE FVLRLEGVIE KVNWDQDPKP ALVTKFMENG SLSGLLQSQC PRPWPLLCRL LKEVVLGMFY LHDQNPVLLH RDLKPSNVLL DPELHVKLAD FGLSTFQGGS QSGTGSGEPG GTLGYLAPEL FVNVNRKAST ASDVYSFGIL MWAVLAGREV ELPTEPSLVY EAVCNRQNRP SLAELPQAGP ETPGLEGLKE LMQLCWSSEP KDRPSFQECL PKTDEVFQMV ENNMNAAVST VKDFLSQLRS SNRRFSIPES GQGGTEMDGF RRTIENQHSR NDVMVSEWLN KLNLEEPPSS VPKKCPSLTK RSRAQEEQVP QAWTAGTSSD SMAQPPQTPE TSTFRNQMPS PTSTGTPSPG PRGNQGAERQ GMNWSCRTPE PNPVTGRPLV NIYNCSGVQV GDNNYLTMQQ TTALPTWGLA PSGKGRGLQH PPPVGSQEGP KDPEAWSRPQ GWYNHSGK //