RIPK3_MOUSE
ID RIPK3_MOUSE Reviewed; 486 AA.
AC Q9QZL0; G3X8V8; Q3U3Z9; Q8K2Y2;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 19-FEB-2014, sequence version 2.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=Receptor-interacting serine/threonine-protein kinase 3 {ECO:0000303|PubMed:19590578};
DE EC=2.7.11.1 {ECO:0000269|PubMed:10490590, ECO:0000269|PubMed:24095729, ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175};
DE AltName: Full=RIP-like protein kinase 3 {ECO:0000303|PubMed:10490590};
DE AltName: Full=Receptor-interacting protein 3 {ECO:0000303|PubMed:10490590};
DE Short=RIP-3 {ECO:0000303|PubMed:10490590};
DE Short=mRIP3 {ECO:0000303|PubMed:10490590};
GN Name=Ripk3 {ECO:0000303|PubMed:27321907, ECO:0000312|MGI:MGI:2154952};
GN Synonyms=Rip3 {ECO:0000303|PubMed:19590578};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], ACTIVE SITE, TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF ASP-143.
RC TISSUE=Embryo;
RX PubMed=10490590; DOI=10.1128/mcb.19.10.6500;
RA Pazdernik N.J., Donner D.B., Goebl M.G., Harrington M.A.;
RT "Mouse receptor interacting protein 3 does not contain a caspase-recruiting
RT or a death domain but induces apoptosis and activates NF-kappaB.";
RL Mol. Cell. Biol. 19:6500-6508(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=NOD;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Czech II; TISSUE=Mammary tumor;
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 [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=14749364; DOI=10.1128/mcb.24.4.1464-1469.2004;
RA Newton K., Sun X., Dixit V.M.;
RT "Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell
RT and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like
RT receptors 2 and 4.";
RL Mol. Cell. Biol. 24:1464-1469(2004).
RN [7]
RP INTERACTION WITH MURID HERPESVIRUS 1 RIR1 (MICROBIAL INFECTION), AND
RP MUTAGENESIS OF 448-VAL--GLY-451.
RX PubMed=18442983; DOI=10.1074/jbc.c800051200;
RA Upton J.W., Kaiser W.J., Mocarski E.S.;
RT "Cytomegalovirus M45 cell death suppression requires receptor-interacting
RT protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with
RT RIP1.";
RL J. Biol. Chem. 283:16966-16970(2008).
RN [8]
RP FUNCTION, AND INTERACTION WITH ZBP1.
RX PubMed=19590578; DOI=10.1038/embor.2009.109;
RA Rebsamen M., Heinz L.X., Meylan E., Michallet M.C., Schroder K.,
RA Hofmann K., Vazquez J., Benedict C.A., Tschopp J.;
RT "DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs
RT to activate NF-kappaB.";
RL EMBO Rep. 10:916-922(2009).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [11]
RP MUTAGENESIS OF SER-232.
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 [12]
RP FUNCTION, AND INTERACTION WITH ZBP1.
RX PubMed=22423968; DOI=10.1016/j.chom.2012.01.016;
RA Upton J.W., Kaiser W.J., Mocarski E.S.;
RT "DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed
RT necrosis that is targeted by murine cytomegalovirus vIRA.";
RL Cell Host Microbe 11:290-297(2012).
RN [13]
RP ERRATUM OF PUBMED:22423968.
RX PubMed=31600504; DOI=10.1016/j.chom.2019.09.004;
RA Upton J.W., Kaiser W.J., Mocarski E.S.;
RT "DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed
RT necrosis that is targeted by murine cytomegalovirus vIRA.";
RL Cell Host Microbe 26:564-564(2019).
RN [14]
RP FUNCTION.
RX PubMed=24019532; DOI=10.1074/jbc.m113.462341;
RA Kaiser W.J., Sridharan H., Huang C., Mandal P., Upton J.W., Gough P.J.,
RA Sehon C.A., Marquis R.W., Bertin J., Mocarski E.S.;
RT "Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL.";
RL J. Biol. Chem. 288:31268-31279(2013).
RN [15]
RP FUNCTION, MUTAGENESIS OF ASP-143, AND INTERACTION WITH MLKL.
RX PubMed=24012422;
RA Murphy J.M., Czabotar P.E., Hildebrand J.M., Lucet I.S., Zhang J.G.,
RA Alvarez-Diaz S., Lewis R., Lalaoui N., Metcalf D., Webb A.I., Young S.N.,
RA Varghese L.N., Tannahill G.M., Hatchell E.C., Majewski I.J., Okamoto T.,
RA Dobson R.C., Hilton D.J., Babon J.J., Nicola N.A., Strasser A., Silke J.,
RA Alexander W.S.;
RT "The pseudokinase MLKL mediates necroptosis via a molecular switch
RT mechanism.";
RL Immunity 39:443-453(2013).
RN [16]
RP PHOSPHORYLATION AT SER-2; SER-165; THR-231; SER-232; THR-257; SER-304;
RP SER-326; THR-338; SER-353; SER-369; SER-380 AND THR-392, INTERACTION WITH
RP MLKL, AND MUTAGENESIS OF THR-231 AND SER-232.
RX PubMed=23612963; DOI=10.1074/jbc.m112.435545;
RA Chen W., Zhou Z., Li L., Zhong C.Q., Zheng X., Wu X., Zhang Y., Ma H.,
RA Huang D., Li W., Xia Z., Han J.;
RT "Diverse sequence determinants control human and mouse receptor interacting
RT protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in
RT necroptotic signaling.";
RL J. Biol. Chem. 288:16247-16261(2013).
RN [17]
RP FUNCTION, ACTIVITY REGULATION, AND DISRUPTION PHENOTYPE.
RX PubMed=24813849; DOI=10.1016/j.cell.2014.04.019;
RA Rickard J.A., O'Donnell J.A., Evans J.M., Lalaoui N., Poh A.R., Rogers T.,
RA Vince J.E., Lawlor K.E., Ninnis R.L., Anderton H., Hall C., Spall S.K.,
RA Phesse T.J., Abud H.E., Cengia L.H., Corbin J., Mifsud S., Di Rago L.,
RA Metcalf D., Ernst M., Dewson G., Roberts A.W., Alexander W.S., Murphy J.M.,
RA Ekert P.G., Masters S.L., Vaux D.L., Croker B.A., Gerlic M., Silke J.;
RT "RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency
RT hematopoiesis.";
RL Cell 157:1175-1188(2014).
RN [18]
RP FUNCTION, ACTIVITY REGULATION, AND DISRUPTION PHENOTYPE.
RX PubMed=24813850; DOI=10.1016/j.cell.2014.04.018;
RA Dillon C.P., Weinlich R., Rodriguez D.A., Cripps J.G., Quarato G.,
RA Gurung P., Verbist K.C., Brewer T.L., Llambi F., Gong Y.N., Janke L.J.,
RA Kelliher M.A., Kanneganti T.D., Green D.R.;
RT "RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3.";
RL Cell 157:1189-1202(2014).
RN [19]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-477, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Embryo;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
RN [20]
RP FUNCTION, ACTIVITY REGULATION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP ASP-161.
RX PubMed=24557836; DOI=10.1126/science.1249361;
RA Newton K., Dugger D.L., Wickliffe K.E., Kapoor N., de Almagro M.C.,
RA Vucic D., Komuves L., Ferrando R.E., French D.M., Webster J.,
RA Roose-Girma M., Warming S., Dixit V.M.;
RT "Activity of protein kinase RIPK3 determines whether cells die by
RT necroptosis or apoptosis.";
RL Science 343:1357-1360(2014).
RN [21]
RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH RIPK1 AND MLKL, DISRUPTION
RP PHENOTYPE, AND MUTAGENESIS OF 448-VAL--GLY-451.
RX PubMed=27321907; DOI=10.1016/j.chom.2016.05.011;
RA Nogusa S., Thapa R.J., Dillon C.P., Liedmann S., Oguin T.H. III,
RA Ingram J.P., Rodriguez D.A., Kosoff R., Sharma S., Sturm O., Verbist K.,
RA Gough P.J., Bertin J., Hartmann B.M., Sealfon S.C., Kaiser W.J.,
RA Mocarski E.S., Lopez C.B., Thomas P.G., Oberst A., Green D.R.,
RA Balachandran S.;
RT "RIPK3 activates parallel pathways of MLKL-driven necroptosis and FADD-
RT mediated apoptosis to protect against influenza A virus.";
RL Cell Host Microbe 20:13-24(2016).
RN [22]
RP FUNCTION, AND INTERACTION WITH ZBP1.
RX PubMed=27746097; DOI=10.1016/j.chom.2016.09.014;
RA Thapa R.J., Ingram J.P., Ragan K.B., Nogusa S., Boyd D.F., Benitez A.A.,
RA Sridharan H., Kosoff R., Shubina M., Landsteiner V.J., Andrake M.,
RA Vogel P., Sigal L.J., tenOever B.R., Thomas P.G., Upton J.W.,
RA Balachandran S.;
RT "DAI senses influenza A virus genomic RNA and activates RIPK3-dependent
RT cell death.";
RL Cell Host Microbe 20:674-681(2016).
RN [23]
RP FUNCTION, ACTIVITY REGULATION, DISRUPTION PHENOTYPE, PHOSPHORYLATION, AND
RP INTERACTION WITH ZBP1 AND RIPK1.
RX PubMed=27819681; DOI=10.1038/nature20558;
RA Lin J., Kumari S., Kim C., Van T.M., Wachsmuth L., Polykratis A.,
RA Pasparakis M.;
RT "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation.";
RL Nature 540:124-128(2016).
RN [24]
RP FUNCTION, ACTIVITY REGULATION, DISRUPTION PHENOTYPE, INTERACTION WITH ZBP1,
RP PHOSPHORYLATION AT THR-231 AND SER-232, AND MUTAGENESIS OF ASP-161 AND
RP 448-VAL--GLY-451.
RX PubMed=27819682; DOI=10.1038/nature20559;
RA Newton K., Wickliffe K.E., Maltzman A., Dugger D.L., Strasser A.,
RA Pham V.C., Lill J.R., Roose-Girma M., Warming S., Solon M., Ngu H.,
RA Webster J.D., Dixit V.M.;
RT "RIPK1 inhibits ZBP1-driven necroptosis during development.";
RL Nature 540:129-133(2016).
RN [25]
RP FUNCTION.
RX PubMed=27917412; DOI=10.1126/sciimmunol.aag2045;
RA Kuriakose T., Man S.M., Malireddi R.K., Karki R., Kesavardhana S.,
RA Place D.E., Neale G., Vogel P., Kanneganti T.D.;
RT "ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3
RT inflammasome and programmed cell death pathways.";
RL Sci. Immunol. 1:0-0(2016).
RN [26]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH ZBP1.
RX PubMed=28607035; DOI=10.15252/embr.201743947;
RA Sridharan H., Ragan K.B., Guo H., Gilley R.P., Landsteiner V.J.,
RA Kaiser W.J., Upton J.W.;
RT "Murine cytomegalovirus IE3-dependent transcription is required for
RT DAI/ZBP1-mediated necroptosis.";
RL EMBO Rep. 18:1429-1441(2017).
RN [27]
RP INTERACTION WITH RIPK1.
RX PubMed=28842570; DOI=10.1038/s41467-017-00406-w;
RA Geng J., Ito Y., Shi L., Amin P., Chu J., Ouchida A.T., Mookhtiar A.K.,
RA Zhao H., Xu D., Shan B., Najafov A., Gao G., Akira S., Yuan J.;
RT "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates
RT apoptosis and necroptosis.";
RL Nat. Commun. 8:359-359(2017).
RN [28]
RP INTERACTION WITH PELI1.
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 [29]
RP INTERACTION WITH MURID HERPESVIRUS 1 RIR1 (MICROBIAL INFECTION).
RX PubMed=30498077; DOI=10.15252/embr.201846518;
RA Pham C.L., Shanmugam N., Strange M., O'Carroll A., Brown J.W., Sierecki E.,
RA Gambin Y., Steain M., Sunde M.;
RT "Viral M45 and necroptosis-associated proteins form heteromeric amyloid
RT assemblies.";
RL EMBO Rep. 20:0-0(2019).
RN [30]
RP FUNCTION.
RX PubMed=30635240; DOI=10.1016/j.immuni.2018.11.017;
RA Daniels B.P., Kofman S.B., Smith J.R., Norris G.T., Snyder A.G., Kolb J.P.,
RA Gao X., Locasale J.W., Martinez J., Gale M. Jr., Loo Y.M., Oberst A.;
RT "The nucleotide sensor ZBP1 and kinase RIPK3 induce the enzyme IRG1 to
RT promote an antiviral metabolic state in neurons.";
RL Immunity 50:64-76(2019).
RN [31]
RP INTERACTION WITH RIPK1.
RX PubMed=31519887; DOI=10.1038/s41467-019-12033-8;
RA Tang Y., Tu H., Zhang J., Zhao X., Wang Y., Qin J., Lin X.;
RT "K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell
RT death during embryogenesis and inflammation.";
RL Nat. Commun. 10:4157-4157(2019).
RN [32]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP DISRUPTION PHENOTYPE, AND INTERACTION WITH ZBP1.
RX PubMed=32200799; DOI=10.1016/j.cell.2020.02.050;
RA Zhang T., Yin C., Boyd D.F., Quarato G., Ingram J.P., Shubina M.,
RA Ragan K.B., Ishizuka T., Crawford J.C., Tummers B., Rodriguez D.A., Xue J.,
RA Peri S., Kaiser W.J., Lopez C.B., Xu Y., Upton J.W., Thomas P.G.,
RA Green D.R., Balachandran S.;
RT "Influenza virus Z-RNAs induce ZBP1-mediated necroptosis.";
RL Cell 180:1115-1129(2020).
RN [33]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=32296175; DOI=10.1038/s41586-020-2129-8;
RA Jiao H., Wachsmuth L., Kumari S., Schwarzer R., Lin J., Eren R.O.,
RA Fisher A., Lane R., Young G.R., Kassiotis G., Kaiser W.J., Pasparakis M.;
RT "Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and
RT inflammation.";
RL Nature 580:391-395(2020).
RN [34]
RP IDENTIFICATION IN THE AIM2 PANOPTOSOME COMPLEX.
RX PubMed=34471287; DOI=10.1038/s41586-021-03875-8;
RA Lee S., Karki R., Wang Y., Nguyen L.N., Kalathur R.C., Kanneganti T.D.;
RT "AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host
RT defence.";
RL Nature 597:415-419(2021).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 1-313 OF MUTANT ALA-111 IN COMPLEX
RP WITH ATP AND MLKL, FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF
RP CYS-111; LYS-230; SER-232 AND GLU-236.
RX PubMed=24095729; DOI=10.1016/j.celrep.2013.08.044;
RA Xie T., Peng W., Yan C., Wu J., Gong X., Shi Y.;
RT "Structural insights into RIP3-mediated necroptotic signaling.";
RL Cell Rep. 5:70-78(2013).
RN [36] {ECO:0007744|PDB:6OKO}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 1-313 IN COMPLEX WITH TYPE II
RP KINASE INHIBITOR, AND ACTIVITY REGULATION.
RX PubMed=32184955; DOI=10.1021/acsmedchemlett.9b00065;
RA Hart A.C., Abell L., Guo J., Mertzman M.E., Padmanabha R., Macor J.E.,
RA Chaudhry C., Lu H., O'Malley K., Shaw P.J., Weigelt C., Pokross M.,
RA Kish K., Kim K.S., Cornelius L., Douglas A.E., Calambur D., Zhang P.,
RA Carpenter B., Pitts W.J.;
RT "Identification of RIPK3 type II inhibitors using high-throughput
RT mechanistic studies in hit triage.";
RL ACS Med. Chem. Lett. 11:266-271(2020).
CC -!- FUNCTION: Serine/threonine-protein kinase that activates necroptosis
CC and apoptosis, two parallel forms of cell death (PubMed:27321907,
CC PubMed:27746097, PubMed:27917412, PubMed:28607035, PubMed:32200799,
CC PubMed:32296175). Necroptosis, a programmed cell death process in
CC response to death-inducing TNF-alpha family members, is triggered by
CC RIPK3 following activation by ZBP1 (PubMed:19590578, PubMed:22423968,
CC PubMed:24012422, PubMed:24019532, PubMed:24557836, PubMed:27746097,
CC PubMed:27819681, PubMed:27819682, PubMed:24095729, PubMed:32200799,
CC PubMed:27321907, PubMed:32296175). 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:24813849, PubMed:24813850, PubMed:27321907). In addition to
CC TNF-induced necroptosis, necroptosis can also take place in the nucleus
CC in 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
CC (PubMed:32200799, PubMed:32296175). Also regulates apoptosis: apoptosis
CC depends on RIPK1, FADD and CASP8, and is independent of MLKL and RIPK3
CC kinase activity (PubMed:27321907). Phosphorylates RIPK1: RIPK1 and
CC RIPK3 undergo reciprocal auto- and trans-phosphorylation (By
CC similarity). In some cell types, also able to restrict viral
CC replication by promoting cell death-independent responses
CC (PubMed:30635240). In response to flavivirus infection in neurons,
CC promotes a cell death-independent pathway that restricts viral
CC replication: together with ZBP1, promotes a death-independent
CC transcriptional program that modifies the cellular metabolism via up-
CC regulation expression of the enzyme ACOD1/IRG1 and production of the
CC metabolite itaconate (PubMed:30635240). Itaconate inhibits the activity
CC of succinate dehydrogenase, generating a metabolic state in neurons
CC that suppresses replication of viral genomes (PubMed:30635240). RIPK3
CC binds to and enhances the activity of three metabolic enzymes: GLUL,
CC GLUD1, and PYGL (By similarity). These metabolic enzymes may eventually
CC stimulate the tricarboxylic acid cycle and oxidative phosphorylation,
CC which could result in enhanced ROS production (By similarity).
CC {ECO:0000250|UniProtKB:Q9Y572, ECO:0000269|PubMed:19590578,
CC ECO:0000269|PubMed:22423968, ECO:0000269|PubMed:24012422,
CC ECO:0000269|PubMed:24019532, ECO:0000269|PubMed:24095729,
CC ECO:0000269|PubMed:24557836, ECO:0000269|PubMed:24813849,
CC ECO:0000269|PubMed:24813850, ECO:0000269|PubMed:27321907,
CC ECO:0000269|PubMed:27746097, ECO:0000269|PubMed:27819681,
CC ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:27917412,
CC ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:30635240,
CC ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175}.
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:10490590, ECO:0000269|PubMed:24095729,
CC ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175};
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:10490590,
CC ECO:0000269|PubMed:24095729, ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175};
CC -!- ACTIVITY REGULATION: Activity is stimulated by ZBP1, which senses
CC double-stranded Z-RNA structures (PubMed:32200799, PubMed:32296175).
CC RIPK3-dependent necroptosis is inhibited by RIPK1: RIPK1 prevents the
CC ZBP1-induced activation of RIPK3 via FADD-mediated recruitment of
CC CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis
CC (PubMed:24813849, PubMed:24813850, PubMed:24557836, PubMed:27321907,
CC PubMed:27819681, PubMed:27819682, PubMed:32296175). Inhibited by type
CC II inhibitor 1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-
CC b]pyridin-4-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide
CC (PubMed:32184955). {ECO:0000269|PubMed:24557836,
CC ECO:0000269|PubMed:24813849, ECO:0000269|PubMed:24813850,
CC ECO:0000269|PubMed:27321907, ECO:0000269|PubMed:27819681,
CC ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:32184955,
CC ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175}.
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:27321907, PubMed:27819681, PubMed:28842570,
CC PubMed:31519887). Interacts with MLKL; the interaction is direct and
CC triggers necroptosis (PubMed:24012422, PubMed:27321907). Interacts with
CC ZBP1 (via RIP homotypic interaction motif); interaction with ZBP1
CC activates RIPK3, triggering necroptosis (PubMed:19590578,
CC PubMed:22423968, PubMed:27746097, PubMed:27819681, PubMed:27819682,
CC PubMed:28607035, PubMed:32200799). Upon TNF-induced necrosis, the
CC RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation
CC of this complex leads to PGAM5 phosphorylation and increase in PGAM5
CC phosphatase activity (By similarity). Binds TRAF2 and is recruited to
CC the TNFR-1 signaling complex (By similarity). Interacts with PYGL, GLUL
CC and GLUD1; these interactions result in activation of these metabolic
CC enzymes (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and
CC XIAP/BIRC4 (By similarity). Interacts with ARHGEF2 (By similarity).
CC Interacts with PELI1 (via atypical FHA domain); the phosphorylated form
CC at Thr-187 binds preferentially to PELI1 (PubMed:29883609). Interacts
CC with BUB1B, TRAF2 and STUB1 (By similarity). Interacts with CASP6 (By
CC similarity). Component of the AIM2 PANoptosome complex, a multiprotein
CC complex that drives inflammatory cell death (PANoptosis)
CC (PubMed:34471287). {ECO:0000250|UniProtKB:Q9Y572,
CC ECO:0000269|PubMed:19590578, ECO:0000269|PubMed:22423968,
CC ECO:0000269|PubMed:24012422, ECO:0000269|PubMed:27321907,
CC ECO:0000269|PubMed:27746097, ECO:0000269|PubMed:27819681,
CC ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:28607035,
CC ECO:0000269|PubMed:28842570, ECO:0000269|PubMed:29883609,
CC ECO:0000269|PubMed:31519887, ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:34471287}.
CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction
CC motif) with murid herpesvirus protein RIR1; this interaction disrupts
CC RIP3-RIP1 interactions characteristic of TNF-alpha induced necroptosis,
CC thereby suppressing this death pathway. {ECO:0000269|PubMed:18442983,
CC ECO:0000269|PubMed:30498077}.
CC -!- INTERACTION:
CC Q9QZL0; Q61160: Fadd; NbExp=6; IntAct=EBI-2367423, EBI-524415;
CC Q9QZL0; Q9D2Y4: Mlkl; NbExp=3; IntAct=EBI-2367423, EBI-5401970;
CC Q9QZL0; Q60855: Ripk1; NbExp=4; IntAct=EBI-2367423, EBI-529119;
CC Q9QZL0; Q9UER7: DAXX; Xeno; NbExp=2; IntAct=EBI-2367423, EBI-77321;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:28607035,
CC ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32296175}. Nucleus
CC {ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175}. Note=Mainly cytoplasmic (PubMed:32200799,
CC PubMed:32296175). Present in the nucleus in response to influenza A
CC virus (IAV) infection (PubMed:32200799). {ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175}.
CC -!- TISSUE SPECIFICITY: Expressed in embryo and in adult spleen, liver,
CC testis, heart, brain and lung. {ECO:0000269|PubMed:10490590}.
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:0000250|UniProtKB:Q9Y572}.
CC -!- PTM: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation
CC (By similarity). Autophosphorylated following interaction with ZBP1
CC (PubMed:27819681). Phosphorylation of Ser-204 plays a role in the
CC necroptotic function of RIPK3 (By similarity). Autophosphorylates at
CC Thr-231 and Ser-232 following activation by ZBP1: phosphorylation at
CC these sites is a hallmark of necroptosis and is required for binding
CC MLKL (PubMed:23612963, PubMed:27819682). Phosphorylation at Thr-187 is
CC important for its kinase activity, interaction with PELI1 and for its
CC ability to mediate TNF-induced necroptosis (By similarity).
CC {ECO:0000250|UniProtKB:Q9Y572, ECO:0000269|PubMed:23612963,
CC ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682}.
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 Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent
CC degradation. {ECO:0000250|UniProtKB:Q9Y572}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype in normal conditions; mice
CC are viable and indistinguishable from wild-type mice (PubMed:14749364,
CC PubMed:24557836). Mice are resistant to TNF-induced hypothermia
CC (PubMed:24557836). Mice are more susceptible to influenza A virus (IAV)
CC infection than wild-type mice: at a modestly lethal dose of IAV, mice
CC display significantly increased rates of mortality, probably caused by
CC a failure to eliminate infected cells and limit virus spread in
CC pulmonary tissue (PubMed:27321907, PubMed:32200799). Perinatal
CC lethality observed in Ripk1 knockout mice is rescued in knockout mice
CC lacking both Ripk1 and Ripk3; mice however die the first days of
CC postnatal life (PubMed:24813849, PubMed:24813850, PubMed:27819681,
CC PubMed:27819682). Only mice lacking Ripk1, Ripk3 and Casp8 survive past
CC weaning and rescue lethality caused by the absence of Ripk1
CC (PubMed:24813849, PubMed:24813850). {ECO:0000269|PubMed:14749364,
CC ECO:0000269|PubMed:24557836, ECO:0000269|PubMed:24813849,
CC ECO:0000269|PubMed:24813850, ECO:0000269|PubMed:27321907,
CC ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682,
CC ECO:0000269|PubMed:32200799}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
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DR EMBL; AF178953; AAF03133.1; -; mRNA.
DR EMBL; AK154505; BAE32636.1; -; mRNA.
DR EMBL; AC098877; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466535; EDL36236.1; -; Genomic_DNA.
DR EMBL; BC029210; AAH29210.1; -; mRNA.
DR CCDS; CCDS27131.1; -.
DR RefSeq; NP_064339.2; NM_019955.2.
DR PDB; 4M66; X-ray; 2.40 A; A/B=1-313.
DR PDB; 4M69; X-ray; 2.50 A; A=1-313.
DR PDB; 6JPD; NMR; -; A/B/C/D/E=409-486.
DR PDB; 6OKO; X-ray; 2.10 A; A/B=1-313.
DR PDBsum; 4M66; -.
DR PDBsum; 4M69; -.
DR PDBsum; 6JPD; -.
DR PDBsum; 6OKO; -.
DR AlphaFoldDB; Q9QZL0; -.
DR SMR; Q9QZL0; -.
DR BioGRID; 208042; 5.
DR DIP; DIP-54883N; -.
DR IntAct; Q9QZL0; 14.
DR MINT; Q9QZL0; -.
DR STRING; 10090.ENSMUSP00000022830; -.
DR iPTMnet; Q9QZL0; -.
DR PhosphoSitePlus; Q9QZL0; -.
DR EPD; Q9QZL0; -.
DR MaxQB; Q9QZL0; -.
DR PaxDb; Q9QZL0; -.
DR PeptideAtlas; Q9QZL0; -.
DR PRIDE; Q9QZL0; -.
DR ProteomicsDB; 253246; -.
DR Antibodypedia; 9228; 939 antibodies from 46 providers.
DR DNASU; 56532; -.
DR Ensembl; ENSMUST00000022830; ENSMUSP00000022830; ENSMUSG00000022221.
DR GeneID; 56532; -.
DR KEGG; mmu:56532; -.
DR UCSC; uc007uav.2; mouse.
DR CTD; 11035; -.
DR MGI; MGI:2154952; Ripk3.
DR VEuPathDB; HostDB:ENSMUSG00000022221; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000160206; -.
DR HOGENOM; CLU_559689_0_0_1; -.
DR InParanoid; Q9QZL0; -.
DR OMA; PFRNQMP; -.
DR OrthoDB; 769579at2759; -.
DR PhylomeDB; Q9QZL0; -.
DR TreeFam; TF106506; -.
DR Reactome; R-MMU-2562578; TRIF-mediated programmed cell death.
DR Reactome; R-MMU-3295583; TRP channels.
DR Reactome; R-MMU-5213460; RIPK1-mediated regulated necrosis.
DR Reactome; R-MMU-5675482; Regulation of necroptotic cell death.
DR Reactome; R-MMU-937041; IKK complex recruitment mediated by RIP1.
DR BioGRID-ORCS; 56532; 1 hit in 73 CRISPR screens.
DR ChiTaRS; Ripk3; mouse.
DR PRO; PR:Q9QZL0; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q9QZL0; protein.
DR Bgee; ENSMUSG00000022221; Expressed in endothelial cell of lymphatic vessel and 160 other tissues.
DR ExpressionAtlas; Q9QZL0; baseline and differential.
DR Genevisible; Q9QZL0; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0004704; F:NF-kappaB-inducing kinase activity; IDA:MGI.
DR GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0032147; P:activation of protein kinase activity; ISS:UniProtKB.
DR GO; GO:1990000; P:amyloid fibril formation; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IMP:ARUK-UCL.
DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB.
DR GO; GO:0097528; P:execution phase of necroptosis; IMP:UniProtKB.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IDA:MGI.
DR GO; GO:0048535; P:lymph node development; IGI:UniProtKB.
DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB.
DR GO; GO:0097527; P:necroptotic signaling pathway; ISO:MGI.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IDA:MGI.
DR GO; GO:0051351; P:positive regulation of ligase activity; IDA:MGI.
DR GO; GO:0060545; P:positive regulation of necroptotic process; IDA:UniProtKB.
DR GO; GO:0010940; P:positive regulation of necrotic cell death; IMP:AgBase.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISO:MGI.
DR GO; GO:0051353; P:positive regulation of oxidoreductase activity; IDA:MGI.
DR GO; GO:0010922; P:positive regulation of phosphatase activity; ISO:MGI.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IMP:UniProtKB.
DR GO; GO:0097300; P:programmed necrotic cell death; IMP:ARUK-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:MGI.
DR GO; GO:0046006; P:regulation of activated T cell proliferation; IGI:UniProtKB.
DR GO; GO:0070235; P:regulation of activation-induced cell death of T cells; IGI:UniProtKB.
DR GO; GO:0002819; P:regulation of adaptive immune response; IGI:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:2000452; P:regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation; IGI:UniProtKB.
DR GO; GO:0032649; P:regulation of interferon-gamma production; IGI:UniProtKB.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IMP:MGI.
DR GO; GO:0001914; P:regulation of T cell mediated cytotoxicity; IGI:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0048536; P:spleen development; IGI:UniProtKB.
DR GO; GO:0033077; P:T cell differentiation in thymus; IGI:UniProtKB.
DR GO; GO:0043029; P:T cell homeostasis; IGI:UniProtKB.
DR GO; GO:0048538; P:thymus development; IGI:UniProtKB.
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 Pfam; PF00069; Pkinase; 1.
DR Pfam; PF12721; RHIM; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; ATP-binding; Cytoplasm; Host-virus interaction;
KW Kinase; Methylation; Necrosis; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Ubl conjugation.
FT CHAIN 1..486
FT /note="Receptor-interacting serine/threonine-protein kinase
FT 3"
FT /id="PRO_0000086611"
FT DOMAIN 22..292
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:24095729, ECO:0007744|PDB:4M69"
FT REGION 312..333
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 349..388
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 462..486
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 440..461
FT /note="RIP homotypic interaction motif (RHIM)"
FT /evidence="ECO:0000269|PubMed:18442983"
FT COMPBIAS 312..326
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 367..386
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 143
FT /note="Proton acceptor"
FT /evidence="ECO:0000305|PubMed:10490590,
FT ECO:0000305|PubMed:24095729"
FT BINDING 28..36
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:24095729, ECO:0007744|PDB:4M69"
FT BINDING 51
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:24095729,
FT ECO:0007744|PDB:4M69"
FT MOD_RES 2
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 165
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 187
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y572"
FT MOD_RES 204
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9Y572"
FT MOD_RES 231
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:23612963,
FT ECO:0000269|PubMed:27819682"
FT MOD_RES 232
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:23612963,
FT ECO:0000269|PubMed:27819682"
FT MOD_RES 257
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 304
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 326
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 338
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 353
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 369
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 380
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 392
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23612963"
FT MOD_RES 477
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MUTAGEN 51
FT /note="K->A: Complete loss of induced necrosis."
FT MUTAGEN 111
FT /note="C->A: No effect."
FT /evidence="ECO:0000269|PubMed:24095729"
FT MUTAGEN 143
FT /note="D->N: Abolishes kinase activity and ability to
FT mediate necroptosis. No autophosphorylation."
FT /evidence="ECO:0000269|PubMed:10490590,
FT ECO:0000269|PubMed:24012422"
FT MUTAGEN 161
FT /note="D->N: Abolished protein kinase activity and ability
FT to activate necroptosis. Knockin mice die during
FT embryogenesis due to constitutive Ripk1- and Casp8-
FT dependent apoptosis. Perinatal lethality observed in Ripk1
FT knockout mice is rescued in knockin mice carrying this
FT mutation."
FT /evidence="ECO:0000269|PubMed:24557836,
FT ECO:0000269|PubMed:27819682"
FT MUTAGEN 230
FT /note="K->A: Slightly affects interaction with MLKL; when
FT associated with A-236. Affects interaction with MLKL; when
FT associated with A-232 and A-236."
FT /evidence="ECO:0000269|PubMed:24095729"
FT MUTAGEN 231
FT /note="T->A: Abolishes ability to mediate necroptosis."
FT /evidence="ECO:0000269|PubMed:23612963"
FT MUTAGEN 232
FT /note="S->A: Abolishes ability to mediate necroptosis.
FT Affects interaction with MLKL; when associated with A-230
FT and A-236."
FT /evidence="ECO:0000269|PubMed:22265413,
FT ECO:0000269|PubMed:23612963, ECO:0000269|PubMed:24095729"
FT MUTAGEN 236
FT /note="E->A: Slightly affects interaction with MLKL; when
FT associated with A-230. Affects interaction with MLKL; when
FT associated with A-230 and A-232."
FT /evidence="ECO:0000269|PubMed:24095729"
FT MUTAGEN 448..451
FT /note="VQIG->AAAA: In RIPK3(RHIM); abolished interaction
FT with ZBP1 and subsequent necroptosis. Perinatal lethality
FT observed in Ripk1 knockout mice is rescued in knockin mice
FT carrying this mutation."
FT /evidence="ECO:0000269|PubMed:18442983,
FT ECO:0000269|PubMed:27819682"
FT CONFLICT 136
FT /note="N -> D (in Ref. 1; AAF03133 and 2; BAE32636)"
FT /evidence="ECO:0000305"
FT CONFLICT 198
FT /note="D -> K (in Ref. 1; AAF03133 and 2; BAE32636)"
FT /evidence="ECO:0000305"
FT CONFLICT 198
FT /note="D -> N (in Ref. 5; AAH29210)"
FT /evidence="ECO:0000305"
FT CONFLICT 283
FT /note="D -> G (in Ref. 2; BAE32636)"
FT /evidence="ECO:0000305"
FT CONFLICT 471
FT /note="D -> G (in Ref. 2; BAE32636)"
FT /evidence="ECO:0000305"
FT HELIX 19..21
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 22..33
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 35..41
FT /evidence="ECO:0007829|PDB:6OKO"
FT TURN 42..45
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 46..53
FT /evidence="ECO:0007829|PDB:6OKO"
FT TURN 55..57
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 58..65
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 78..80
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 83..85
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 88..96
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 103..106
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 115..133
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 135..137
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 146..148
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 149..151
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 157..159
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 164..167
FT /evidence="ECO:0007829|PDB:4M69"
FT HELIX 188..190
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 193..196
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 205..221
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 231..237
FT /evidence="ECO:0007829|PDB:4M69"
FT TURN 238..241
FT /evidence="ECO:0007829|PDB:4M69"
FT HELIX 247..249
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 255..257
FT /evidence="ECO:0007829|PDB:4M69"
FT HELIX 260..270
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 275..277
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 281..295
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 296..298
FT /evidence="ECO:0007829|PDB:6OKO"
FT HELIX 299..310
FT /evidence="ECO:0007829|PDB:6OKO"
FT STRAND 445..450
FT /evidence="ECO:0007829|PDB:6JPD"
SQ SEQUENCE 486 AA; 53322 MW; 31C5EEE77F55778B CRC64;
MSSVKLWPTG ASAVPLVSRE ELKKLEFVGK GGFGVVFRAH HRTWNHDVAV KIVNSKKISW
EVKAMVNLRN ENVLLLLGVT EDLQWDFVSG QALVTRFMEN GSLAGLLQPE CPRPWPLLCR
LLQEVVLGMC YLHSLNPPLL HRDLKPSNIL LDPELHAKLA DFGLSTFQGG SQSGSGSGSG
SRDSGGTLAY LDPELLFDVN LKASKASDVY SFGILVWAVL AGREAELVDK TSLIRETVCD
RQSRPPLTEL PPGSPETPGL EKLKELMIHC WGSQSENRPS FQDCEPKTNE VYNLVKDKVD
AAVSEVKHYL SQHRSSGRNL SAREPSQRGT EMDCPRETMV SKMLDRLHLE EPSGPVPGKC
PERQAQDTSV GPATPARTSS DPVAGTPQIP HTLPFRGTTP GPVFTETPGP HPQRNQGDGR
HGTPWYPWTP PNPMTGPPAL VFNNCSEVQI GNYNSLVAPP RTTASSSAKY DQAQFGRGRG
WQPFHK
