RIPK3_HUMAN
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 03-AUG-2022, entry version 204.
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: sars3a; 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}.
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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 SMR; Q9Y572; -.
DR BioGRID; 116224; 60.
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 GlyGen; Q9Y572; 1 site, 1 O-linked glycan (1 site).
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; Q9Y572; -.
DR PeptideAtlas; Q9Y572; -.
DR PRIDE; 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; 939 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 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; PFRNQMP; -.
DR OrthoDB; 769579at2759; -.
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 SignaLink; Q9Y572; -.
DR SIGNOR; Q9Y572; -.
DR BioGRID-ORCS; 11035; 29 hits in 1106 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 92 other tissues.
DR ExpressionAtlas; Q9Y572; baseline and differential.
DR Genevisible; Q9Y572; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
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:0004704; F:NF-kappaB-inducing kinase activity; IEA:Ensembl.
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; ISS:UniProtKB.
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:0007249; P:I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
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; IMP:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0051351; P:positive regulation of ligase activity; 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:0051353; P:positive regulation of oxidoreductase activity; IEA:Ensembl.
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:0032649; P:regulation of interferon-gamma production; ISS:UniProtKB.
DR GO; GO:0001914; P:regulation of T cell mediated cytotoxicity; 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 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; 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 PELI1-
FT mediated ubiquitination. No loss of interaction with RIPK1
FT and MLKL."
FT /evidence="ECO:0000269|PubMed:29883609"
FT MUTAGEN 185
FT /note="Y->A,F: Loss of interaction with PELI1 and PELI1-
FT 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
