RIPK1_HUMAN
ID RIPK1_HUMAN Reviewed; 671 AA.
AC Q13546; A0AV89; B2RAG1; B4E3F9; Q13180; Q59H33;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-2005, sequence version 3.
DT 03-AUG-2022, entry version 226.
DE RecName: Full=Receptor-interacting serine/threonine-protein kinase 1;
DE EC=2.7.11.1 {ECO:0000269|PubMed:23473668, ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:8612133};
DE AltName: Full=Cell death protein RIP {ECO:0000303|PubMed:8612133};
DE AltName: Full=Receptor-interacting protein 1 {ECO:0000303|PubMed:16603398};
DE Short=RIP-1 {ECO:0000303|PubMed:16603398};
GN Name=RIPK1 {ECO:0000312|HGNC:HGNC:10019};
GN Synonyms=RIP {ECO:0000303|PubMed:8612133},
GN RIP1 {ECO:0000303|PubMed:16603398};
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), CATALYTIC ACTIVITY,
RP AUTOPHOSPHORYLATION, MUTAGENESIS OF LYS-45, INTERACTION WITH TRADD; TRAF1;
RP TRAF2 AND TRAF3, AND VARIANT VAL-438.
RC TISSUE=Umbilical vein endothelial cell;
RX PubMed=8612133; DOI=10.1016/s1074-7613(00)80252-6;
RA Hsu H., Huang J., Shu H.-B., Baichwal V.R., Goeddel D.V.;
RT "TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1
RT signaling complex.";
RL Immunity 4:387-396(1996).
RN [2]
RP SEQUENCE REVISION TO 120.
RA Huang J., Hsu H., Baichwal V.R., Goeddel D.V.;
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 15-671 (ISOFORM 2).
RC TISSUE=Adrenal gland, and Uterus;
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 [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LYS-234.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT VAL-438.
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 153-671.
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RT "Homo sapiens protein coding cDNA.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 300-671, AND VARIANT VAL-438.
RC TISSUE=Leukemic T-cell;
RX PubMed=7538908; DOI=10.1016/0092-8674(95)90072-1;
RA Stanger B.Z., Leder P., Lee T.-H., Kim E., Seed B.;
RT "RIP: a novel protein containing a death domain that interacts with
RT Fas/APO-1 (CD95) in yeast and causes cell death.";
RL Cell 81:513-523(1995).
RN [9]
RP INTERACTION WITH CRADD, AND DOMAIN.
RX PubMed=9044836;
RA Ahmad M., Srinivasula S.M., Wang L., Talanian R.V., Litwack G.,
RA Fernandes-Alnemri T., Alnemri E.S.;
RT "CRADD, a novel human apoptotic adaptor molecule for caspase-2, and
RT FasL/tumor necrosis factor receptor-interacting protein RIP.";
RL Cancer Res. 57:615-619(1997).
RN [10]
RP CLEAVAGE BY CASP8, AND MUTAGENESIS OF ASP-324.
RX PubMed=10521396; DOI=10.1101/gad.13.19.2514;
RA Lin Y., Devin A., Rodriguez Y., Liu Z.-G.;
RT "Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced
RT apoptosis.";
RL Genes Dev. 13:2514-2526(1999).
RN [11]
RP INTERACTION WITH SQSTM1 AND TRAF2, AND DOMAIN DEATH.
RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044;
RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.;
RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB
RT activation.";
RL EMBO J. 18:3044-3053(1999).
RN [12]
RP INTERACTION WITH RIPK3.
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 [13]
RP INTERACTION WITH BNLF1.
RX PubMed=10409763; DOI=10.1128/mcb.19.8.5759;
RA Izumi K.M., Cahir McFarland E., Ting A.T., Riley E.A., Seed B., Kieff E.D.;
RT "The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the
RT tumor necrosis factor receptor-associated proteins TRADD and receptor-
RT interacting protein (RIP) but does not induce apoptosis or require RIP for
RT NF-kappaB activation.";
RL Mol. Cell. Biol. 19:5759-5767(1999).
RN [14]
RP INTERACTION WITH IKBKG.
RX PubMed=9927690; DOI=10.1073/pnas.96.3.1042;
RA Li Y., Kang J., Friedman J., Tarassishin L., Ye J., Kovalenko A.,
RA Wallach D., Horwitz M.S.;
RT "Identification of a cell protein (FIP-3) as a modulator of NF-kappaB
RT activity and as a target of an adenovirus inhibitor of tumor necrosis
RT factor alpha-induced apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:1042-1047(1999).
RN [15]
RP FUNCTION.
RX PubMed=11101870; DOI=10.1038/82732;
RA Holler N., Zaru R., Micheau O., Thome M., Attinger A., Valitutti S.,
RA Bodmer J.L., Schneider P., Seed B., Tschopp J.;
RT "Fas triggers an alternative, caspase-8-independent cell death pathway
RT using the kinase RIP as effector molecule.";
RL Nat. Immunol. 1:489-495(2000).
RN [16]
RP INTERACTION WITH EGFR.
RX PubMed=11116146; DOI=10.1074/jbc.m008458200;
RA Habib A.A., Chatterjee S., Park S.-K., Ratan R.R., Lefebvre S.,
RA Vartanian T.;
RT "The epidermal growth factor receptor engages receptor interacting protein
RT and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-
RT kappa B. Identification of a novel receptor-tyrosine kinase signalosome.";
RL J. Biol. Chem. 276:8865-8874(2001).
RN [17]
RP INTERACTION WITH RNF216.
RX PubMed=11854271; DOI=10.1074/jbc.m108675200;
RA Chen D., Li X., Zhai Z., Shu H.-B.;
RT "A novel zinc finger protein interacts with receptor-interacting protein
RT (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B
RT activation.";
RL J. Biol. Chem. 277:15985-15991(2002).
RN [18]
RP RIP HOMOTYPIC INTERACTION MOTIF, AND INTERACTION WITH RIPK3.
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 [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-384, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=15144186; DOI=10.1021/ac035352d;
RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,
RA Peters E.C.;
RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from
RT human T cells using immobilized metal affinity chromatography and tandem
RT mass spectrometry.";
RL Anal. Chem. 76:2763-2772(2004).
RN [20]
RP INTERACTION WITH ZFAND5.
RX PubMed=14754897; DOI=10.1074/jbc.m309491200;
RA Huang J., Teng L., Li L., Liu T., Li L., Chen D., Xu L.-G., Zhai Z.,
RA Shu H.-B.;
RT "ZNF216 is an A20-like and IkappaB kinase gamma-interacting inhibitor of
RT NFkappaB activation.";
RL J. Biol. Chem. 279:16847-16853(2004).
RN [21]
RP INTERACTION WITH DAB2IP.
RX PubMed=15310755; DOI=10.1074/jbc.m407617200;
RA Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.;
RT "AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-
RT induced ASK1-JNK activation.";
RL J. Biol. Chem. 279:44955-44965(2004).
RN [22]
RP UBIQUITINATION BY TRAF2, AND DEUBIQUITINATION BY TNFAIP3.
RX PubMed=15258597; DOI=10.1038/nature02794;
RA Wertz I.E., O'Rourke K.M., Zhou H., Eby M., Aravind L., Seshagiri S.,
RA Wu P., Wiesmann C., Baker R., Boone D.L., Ma A., Koonin E.V., Dixit V.M.;
RT "De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-
RT kappaB signalling.";
RL Nature 430:694-699(2004).
RN [23]
RP INTERACTION WITH MAVS.
RX PubMed=16127453; DOI=10.1038/ni1243;
RA Kawai T., Takahashi K., Sato S., Coban C., Kumar H., Kato H., Ishii K.J.,
RA Takeuchi O., Akira S.;
RT "IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon
RT induction.";
RL Nat. Immunol. 6:981-988(2005).
RN [24]
RP UBIQUITINATION AT LYS-377, AND MUTAGENESIS OF LYS-377.
RX PubMed=16603398; DOI=10.1016/j.molcel.2006.03.026;
RA Ea C.K., Deng L., Xia Z.P., Pineda G., Chen Z.J.;
RT "Activation of IKK by TNFalpha requires site-specific ubiquitination of
RT RIP1 and polyubiquitin binding by NEMO.";
RL Mol. Cell 22:245-257(2006).
RN [25]
RP REVIEW.
RX PubMed=17301840; DOI=10.1038/sj.cdd.4402085;
RA Festjens N., Vanden Berghe T., Cornelis S., Vandenabeele P.;
RT "RIP1, a kinase on the crossroads of a cell's decision to live or die.";
RL Cell Death Differ. 14:400-410(2007).
RN [26]
RP FUNCTION IN PHOSPHORYLATION OF DAB2IP, AND INTERACTION WITH DAB2IP.
RX PubMed=17389591; DOI=10.1074/jbc.m701148200;
RA Zhang H., Zhang H., Lin Y., Li J., Pober J.S., Min W.;
RT "RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical
RT for tumor necrosis factor-induced ASK1-JNK/p38 activation.";
RL J. Biol. Chem. 282:14788-14796(2007).
RN [27]
RP INTERACTION WITH RBCK1.
RX PubMed=17449468; DOI=10.1074/jbc.m701913200;
RA Tian Y., Zhang Y., Zhong B., Wang Y.Y., Diao F.C., Wang R.P., Zhang M.,
RA Chen D.Y., Zhai Z.H., Shu H.B.;
RT "RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-
RT triggered NF-kappaB activation by targeting TAB2/3 for degradation.";
RL J. Biol. Chem. 282:16776-16782(2007).
RN [28]
RP INTERACTION WITH RFFL, AND UBIQUITINATION BY RFFL.
RX PubMed=18450452; DOI=10.1016/j.cub.2008.04.017;
RA Liao W., Xiao Q., Tchikov V., Fujita K., Yang W., Wincovitch S.,
RA Garfield S., Conze D., El-Deiry W.S., Schuetze S., Srinivasula S.M.;
RT "CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates
RT TNF-induced NF-kappaB activation.";
RL Curr. Biol. 18:641-649(2008).
RN [29]
RP MUTAGENESIS OF SER-161, INHIBITION BY NECROSTATIN-1, AND PHOSPHORYLATION AT
RP SER-6; SER-20; SER-25; SER-161; SER-166; SER-303; SER-320 AND SER-333.
RX PubMed=18408713; DOI=10.1038/nchembio.83;
RA Degterev A., Hitomi J., Germscheid M., Ch'en I.L., Korkina O., Teng X.,
RA Abbott D., Cuny G.D., Yuan C., Wagner G., Hedrick S.M., Gerber S.A.,
RA Lugovskoy A., Yuan J.;
RT "Identification of RIP1 kinase as a specific cellular target of
RT necrostatins.";
RL Nat. Chem. Biol. 4:313-321(2008).
RN [30]
RP INTERACTION WITH MURID HERPESVIRUS 1 PROTEIN RIR1.
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 [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [32]
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 [33]
RP FUNCTION, AND INTERACTION WITH RIPK3.
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 [34]
RP INTERACTION WITH RNF34, AND UBIQUITINATION BY RNF34.
RX DOI=10.1016/j.cub.2008.11.041;
RA Liao W., Fujita K., Xiao Q., Tchikov V., Yang W., Gunsor M., Garfield S.,
RA Goldsmith P., El-Deiry W.S., Schuetze S., Srinivasula S.M.;
RT "Response: CARP1 regulates induction of NF-kappaB by TNFalpha.";
RL Curr. Biol. 19:R17-R19(2009).
RN [35]
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 [36]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [37]
RP UBIQUITINATION BY THE LUBAC COMPLEX.
RX PubMed=21455173; DOI=10.1038/nature09816;
RA Gerlach B., Cordier S.M., Schmukle A.C., Emmerich C.H., Rieser E.,
RA Haas T.L., Webb A.I., Rickard J.A., Anderton H., Wong W.W., Nachbur U.,
RA Gangoda L., Warnken U., Purcell A.W., Silke J., Walczak H.;
RT "Linear ubiquitination prevents inflammation and regulates immune
RT signalling.";
RL Nature 471:591-596(2011).
RN [38]
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 [39]
RP IDENTIFICATION IN COMPLEX WITH PGAM5; RIPK3 AND MLKL.
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 [40]
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 [41]
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=22858542; DOI=10.1038/cdd.2012.98;
RA van Raam B.J., Ehrnhoefer D.E., Hayden M.R., Salvesen G.S.;
RT "Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-
RT 6.";
RL Cell Death Differ. 20:86-96(2013).
RN [42]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [43]
RP GLYCOSYLATION AT ARG-603 (MICROBIAL INFECTION).
RX PubMed=23955153; DOI=10.1038/nature12436;
RA Li S., Zhang L., Yao Q., Li L., Dong N., Rong J., Gao W., Ding X., Sun L.,
RA Chen X., Chen S., Shao F.;
RT "Pathogen blocks host death receptor signalling by arginine GlcNAcylation
RT of death domains.";
RL Nature 501:242-246(2013).
RN [44]
RP INTERACTION WITH TNFRSF1A.
RX PubMed=24130170; DOI=10.1093/carcin/bgt338;
RA Kim T.W., Kang Y.K., Park Z.Y., Kim Y.H., Hong S.W., Oh S.J., Sohn H.A.,
RA Yang S.J., Jang Y.J., Lee D.C., Kim S.Y., Yoo H.S., Kim E., Yeom Y.I.,
RA Park K.C.;
RT "SH3RF2 functions as an oncogene by mediating PAK4 protein stability.";
RL Carcinogenesis 35:624-634(2014).
RN [45]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [46]
RP REVIEW.
RX PubMed=25459879; DOI=10.1016/j.molcel.2014.11.001;
RA Weinlich R., Green D.R.;
RT "The two faces of receptor interacting protein kinase-1.";
RL Mol. Cell 56:469-480(2014).
RN [47]
RP INTERACTION WITH TICAM1.
RX PubMed=25736436; DOI=10.15252/embr.201439637;
RA Hu Y.H., Zhang Y., Jiang L.Q., Wang S., Lei C.Q., Sun M.S., Shu H.B.,
RA Liu Y.;
RT "WDFY1 mediates TLR3/4 signaling by recruiting TRIF.";
RL EMBO Rep. 16:447-455(2015).
RN [48]
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 [49]
RP INTERACTION WITH MUMPS VIRUS PROTEIN SH (MICROBIAL INFECTION).
RX PubMed=28659487; DOI=10.1128/jvi.01037-17;
RA Franz S., Rennert P., Woznik M., Gruetzke J., Luedde A., Arriero Pais E.M.,
RA Finsterbusch T., Geyer H., Mankertz A., Friedrich N.;
RT "Mumps virus SH protein inhibits NF-kappaB activation by interacting with
RT tumor necrosis factor receptor 1, interleukin-1 receptor 1, and Toll-like
RT receptor 3 complexes.";
RL J. Virol. 91:0-0(2017).
RN [50]
RP INTERACTION WITH PELI1 AND RIPK3, AND UBIQUITINATION BY 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 [51]
RP FUNCTION, SUBUNIT, MUTAGENESIS OF LYS-599, AND PHOSPHORYLATION AT SER-166.
RX PubMed=29440439; DOI=10.1073/pnas.1722013115;
RA Meng H., Liu Z., Li X., Wang H., Jin T., Wu G., Shan B.,
RA Christofferson D.E., Qi C., Yu Q., Li Y., Yuan J.;
RT "Death-domain dimerization-mediated activation of RIPK1 controls
RT necroptosis and RIPK1-dependent apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E2001-E2009(2018).
RN [52]
RP INVOLVEMENT IN IMD57.
RX PubMed=30026316; DOI=10.1126/science.aar2641;
RA Cuchet-Lourenco D., Eletto D., Wu C., Plagnol V., Papapietro O., Curtis J.,
RA Ceron-Gutierrez L., Bacon C.M., Hackett S., Alsaleem B., Maes M.,
RA Gaspar M., Alisaac A., Goss E., AlIdrissi E., Siegmund D., Wajant H.,
RA Kumararatne D., AlZahrani M.S., Arkwright P.D., Abinun M., Doffinger R.,
RA Nejentsev S.;
RT "Biallelic RIPK1 mutations in humans cause severe immunodeficiency,
RT arthritis, and intestinal inflammation.";
RL Science 361:810-813(2018).
RN [53]
RP REVIEW.
RX PubMed=31457011; DOI=10.3389/fcell.2019.00163;
RA Ang R.L., Chan M., Ting A.T.;
RT "Ripoptocide - A Spark for Inflammation.";
RL Front. Cell Dev. Biol. 7:163-163(2019).
RN [54]
RP FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT SER-25, AND MUTAGENESIS OF
RP SER-25 AND LYS-45.
RX PubMed=30988283; DOI=10.1038/s41467-019-09690-0;
RA Dondelinger Y., Delanghe T., Priem D., Wynosky-Dolfi M.A., Sorobetea D.,
RA Rojas-Rivera D., Giansanti P., Roelandt R., Gropengiesser J.,
RA Ruckdeschel K., Savvides S.N., Heck A.J.R., Vandenabeele P., Brodsky I.E.,
RA Bertrand M.J.M.;
RT "Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in
RT models of infection and inflammation.";
RL Nat. Commun. 10:1729-1729(2019).
RN [55]
RP FUNCTION, PROTEOLYTIC CLEAVAGE (MICROBIAL INFECTION), AND MUTAGENESIS OF
RP 539-ILE--GLY-542.
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 [56]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-294 IN COMPLEXES WITH
RP NECROSTATIN-TYPE INHIBITORS, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND
RP AUTOPHOSPHORYLATION.
RX PubMed=23473668; DOI=10.1016/j.str.2013.01.016;
RA Xie T., Peng W., Liu Y., Yan C., Maki J., Degterev A., Yuan J., Shi Y.;
RT "Structural basis of RIP1 inhibition by necrostatins.";
RL Structure 21:493-499(2013).
RN [57] {ECO:0007744|PDB:5V7Z}
RP STRUCTURE BY NMR OF 532-549 IN COMPLEX WITH RIPK3, SUBUNIT, INTERACTION
RP WITH RIPK3, DOMAIN, AND MUTAGENESIS OF SER-536.
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).
RN [58] {ECO:0007744|PDB:6AC5}
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 561-671, GLYCOSYLATION AT ARG-603
RP (MICROBIAL INFECTION), AND MUTAGENESIS OF ARG-603.
RX PubMed=30979585; DOI=10.1016/j.molcel.2019.03.028;
RA Ding J., Pan X., Du L., Yao Q., Xue J., Yao H., Wang D.C., Li S., Shao F.;
RT "Structural and functional insights into host death domains inactivation by
RT the bacterial arginine GlcNAcyltransferase effector.";
RL Mol. Cell 74:922-935(2019).
RN [59]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-64; ILE-81; VAL-220; SER-404; VAL-443
RP AND VAL-569.
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 [60]
RP INVOLVEMENT IN AIEFL, VARIANTS AIEFL ASN-324; HIS-324 AND TYR-324,
RP CHARACTERIZATION OF VARIANTS AIEFL ASN-324; HIS-324 AND TYR-324, CLEAVAGE
RP BY CASP8, AND FUNCTION.
RX PubMed=31827281; DOI=10.1038/s41586-019-1828-5;
RA Lalaoui N., Boyden S.E., Oda H., Wood G.M., Stone D.L., Chau D., Liu L.,
RA Stoffels M., Kratina T., Lawlor K.E., Zaal K.J.M., Hoffmann P.M.,
RA Etemadi N., Shield-Artin K., Biben C., Tsai W.L., Blake M.D., Kuehn H.S.,
RA Yang D., Anderton H., Silke N., Wachsmuth L., Zheng L., Moura N.S.,
RA Beck D.B., Gutierrez-Cruz G., Ombrello A.K., Pinto-Patarroyo G.P.,
RA Kueh A.J., Herold M.J., Hall C., Wang H., Chae J.J., Dmitrieva N.I.,
RA McKenzie M., Light A., Barham B.K., Jones A., Romeo T.M., Zhou Q.,
RA Aksentijevich I., Mullikin J.C., Gross A.J., Shum A.K., Hawkins E.D.,
RA Masters S.L., Lenardo M.J., Boehm M., Rosenzweig S.D., Pasparakis M.,
RA Voss A.K., Gadina M., Kastner D.L., Silke J.;
RT "Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory
RT disease.";
RL Nature 577:103-108(2020).
RN [61]
RP INVOLVEMENT IN AIEFL, VARIANTS AIEFL HIS-324 AND VAL-324, CHARACTERIZATION
RP OF VARIANTS AIEFL HIS-324 AND VAL-324, FUNCTION, CATALYTIC ACTIVITY,
RP AUTOPHOSPHORYLATION, PHOSPHORYLATION AT SER-166, AND CLEAVAGE BY CASP8.
RX PubMed=31827280; DOI=10.1038/s41586-019-1830-y;
RA Tao P., Sun J., Wu Z., Wang S., Wang J., Li W., Pan H., Bai R., Zhang J.,
RA Wang Y., Lee P.Y., Ying W., Zhou Q., Hou J., Wang W., Sun B., Yang M.,
RA Liu D., Fang R., Han H., Yang Z., Huang X., Li H., Deuitch N., Zhang Y.,
RA Dissanayake D., Haude K., McWalter K., Roadhouse C., MacKenzie J.J.,
RA Laxer R.M., Aksentijevich I., Yu X., Wang X., Yuan J., Zhou Q.;
RT "A dominant autoinflammatory disease caused by non-cleavable variants of
RT RIPK1.";
RL Nature 577:109-114(2020).
CC -!- FUNCTION: Serine-threonine kinase which is a key regulator of TNF-
CC mediated apoptosis, necroptosis and inflammatory pathways
CC (PubMed:32657447, PubMed:31827280, PubMed:31827281). Exhibits kinase
CC activity-dependent functions that regulate cell death and kinase-
CC independent scaffold functions regulating inflammatory signaling and
CC cell survival (PubMed:11101870, PubMed:19524512, PubMed:19524513,
CC PubMed:29440439, PubMed:30988283). Has kinase-independent scaffold
CC functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-
CC R1 signaling complex (TNF-RSC also known as complex I) where it acts as
CC a scaffold protein promoting cell survival, in part, by activating the
CC canonical NF-kappa-B pathway (By similarity). Kinase activity is
CC essential to regulate necroptosis and apoptosis, two parallel forms of
CC cell death: upon activation of its protein kinase activity, regulates
CC assembly of two death-inducing complexes, namely complex IIa (RIPK1-
CC FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-
CC MLKL), which drives necroptosis (By similarity). RIPK1 is required to
CC limit CASP8-dependent TNFR1-induced apoptosis (By similarity). In
CC normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent
CC necroptosis, a process mediated by RIPK3 component of complex IIb,
CC which catalyzes phosphorylation of MLKL upon induction by ZBP1
CC (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283).
CC Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of
CC CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis
CC (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283).
CC Required to inhibit apoptosis and necroptosis during embryonic
CC development: acts by preventing the interaction of TRADD with FADD
CC thereby limiting aberrant activation of CASP8 (By similarity). In
CC addition to apoptosis and necroptosis, also involved in inflammatory
CC response by promoting transcriptional production of pro-inflammatory
CC cytokines, such as interleukin-6 (IL6) (PubMed:31827280,
CC PubMed:31827281). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo
CC reciprocal auto- and trans-phosphorylation (PubMed:19524513).
CC Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and
CC thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591,
CC PubMed:15310755). Required for ZBP1-induced NF-kappa-B activation in
CC response to DNA damage (By similarity). {ECO:0000250|UniProtKB:Q60855,
CC ECO:0000269|PubMed:11101870, ECO:0000269|PubMed:15310755,
CC ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:19524512,
CC ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:29440439,
CC ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31827280,
CC ECO:0000269|PubMed:31827281, ECO:0000269|PubMed:32657447}.
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:23473668, ECO:0000269|PubMed:30988283,
CC ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:8612133};
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:23473668,
CC ECO:0000269|PubMed:30988283, ECO:0000269|PubMed:31827280,
CC ECO:0000269|PubMed:8612133};
CC -!- ACTIVITY REGULATION: Serine-threonine kinase activity is inhibited by
CC linear polyubiquitination ('Met-1'-linked) by the LUBAC complex (By
CC similarity). Inhibited by necrostatins, including necrostatin-1,
CC necrostatin-3 and necrostatin-4 (PubMed:23473668).
CC {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:23473668}.
CC -!- SUBUNIT: Homodimer (PubMed:29440439, PubMed:29681455). Interacts (via
CC RIP homotypic interaction motif) with RIPK3 (via RIP homotypic
CC interaction motif); this interaction induces RIPK1 phosphorylation and
CC formation of a RIPK1-RIPK3 necroptosis-inducing complex
CC (PubMed:11734559, PubMed:29883609, PubMed:19524512, PubMed:10358032,
CC PubMed:29681455). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer
CC further interacts with PGAM5 and MLKL; the formation of this complex
CC leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase
CC activity (PubMed:22265414). Interacts (via the death domain) with
CC TNFRSF6 (via the death domain) and TRADD (via the death domain)
CC (PubMed:8612133). Is recruited by TRADD to TNFRSF1A in a TNF-dependent
CC process (PubMed:24130170). Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and
CC TRAF3 (PubMed:8612133, PubMed:9927690, PubMed:11854271,
CC PubMed:11116146). Interacts with BNLF1 (PubMed:10409763). Interacts
CC with SQSTM1 upon TNF-alpha stimulation (PubMed:10356400). May interact
CC with MAVS/IPS1 (PubMed:16127453). Interacts with ZFAND5
CC (PubMed:14754897). Interacts with RBCK1 (PubMed:17449468). Interacts
CC with ZBP1 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2
CC and XIAP/BIRC4 (PubMed:21931591). Interacts (via kinase domain) with
CC DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha-
CC dependent manner (PubMed:17389591, PubMed:15310755). Interacts with
CC ARHGEF2 (PubMed:21887730). Interacts (via protein kinase domain) with
CC RFFL; involved in RIPK1 ubiquitination (PubMed:18450452). Interacts
CC with RNF34; involved in RIPK1 ubiquitination (Ref.34). Interacts with
CC TICAM1 and this interaction is enhanced in the presence of WDFY1
CC (PubMed:25736436). Interacts with PELI1 (PubMed:29883609). Interacts
CC (via death domain) with CRADD (via death domain); the interaction is
CC direct (PubMed:9044836). Component of complex IIa composed of at least
CC RIPK1, FADD and CASP8 (By similarity). Component of the AIM2
CC PANoptosome complex, a multiprotein complex that drives inflammatory
CC cell death (PANoptosis) (By similarity). Interacts with MAP3K7, CFLAR,
CC CASP8, FADD and NEMO (By similarity). {ECO:0000250|UniProtKB:Q60855,
CC ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10358032,
CC ECO:0000269|PubMed:10409763, ECO:0000269|PubMed:11116146,
CC ECO:0000269|PubMed:11734559, ECO:0000269|PubMed:11854271,
CC ECO:0000269|PubMed:14754897, ECO:0000269|PubMed:16127453,
CC ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:17449468,
CC ECO:0000269|PubMed:18450452, ECO:0000269|PubMed:19524512,
CC ECO:0000269|PubMed:21887730, ECO:0000269|PubMed:21931591,
CC ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:24130170,
CC ECO:0000269|PubMed:25736436, ECO:0000269|PubMed:29440439,
CC ECO:0000269|PubMed:29681455, ECO:0000269|PubMed:29883609,
CC ECO:0000269|PubMed:8612133, ECO:0000269|PubMed:9044836,
CC ECO:0000269|PubMed:9927690, ECO:0000269|Ref.34}.
CC -!- SUBUNIT: (Microbial infection) Interacts with mumps virus protein SH;
CC this interaction inhibits downstream NF-kappa-B pathway activation.
CC {ECO:0000269|PubMed:28659487}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Murid herpesvirus 1
CC protein RIR1. {ECO:0000269|PubMed:18442983}.
CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction
CC motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP
CC homotypic interaction motif); this interaction prevents necroptosis
CC activation. {ECO:0000269|PubMed:25674983}.
CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction
CC motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP
CC homotypic interaction motif); this interaction prevents necroptosis
CC activation. {ECO:0000269|PubMed:25674983}.
CC -!- INTERACTION:
CC Q13546; P04083: ANXA1; NbExp=5; IntAct=EBI-358507, EBI-354007;
CC Q13546; Q13490: BIRC2; NbExp=5; IntAct=EBI-358507, EBI-514538;
CC Q13546; Q13489: BIRC3; NbExp=3; IntAct=EBI-358507, EBI-517709;
CC Q13546; Q92851: CASP10; NbExp=2; IntAct=EBI-358507, EBI-495095;
CC Q13546; Q14790: CASP8; NbExp=28; IntAct=EBI-358507, EBI-78060;
CC Q13546; Q8IVM0: CCDC50; NbExp=2; IntAct=EBI-358507, EBI-723996;
CC Q13546; P48729: CSNK1A1; NbExp=5; IntAct=EBI-358507, EBI-1383726;
CC Q13546; Q13158: FADD; NbExp=11; IntAct=EBI-358507, EBI-494804;
CC Q13546; Q9Y6K9: IKBKG; NbExp=8; IntAct=EBI-358507, EBI-81279;
CC Q13546; Q9ULZ3: PYCARD; NbExp=2; IntAct=EBI-358507, EBI-751215;
CC Q13546; Q13546: RIPK1; NbExp=10; IntAct=EBI-358507, EBI-358507;
CC Q13546; Q9Y572: RIPK3; NbExp=26; IntAct=EBI-358507, EBI-298250;
CC Q13546; P19438: TNFRSF1A; NbExp=6; IntAct=EBI-358507, EBI-299451;
CC Q13546; Q13077: TRAF1; NbExp=6; IntAct=EBI-358507, EBI-359224;
CC Q13546; Q12933: TRAF2; NbExp=8; IntAct=EBI-358507, EBI-355744;
CC Q13546; Q13114: TRAF3; NbExp=3; IntAct=EBI-358507, EBI-357631;
CC Q13546; Q13107: USP4; NbExp=4; IntAct=EBI-358507, EBI-723290;
CC Q13546; B7UI21: nleB1; Xeno; NbExp=4; IntAct=EBI-358507, EBI-16070376;
CC Q13546; PRO_0000449629 [P0DTD1]: rep; Xeno; NbExp=5; IntAct=EBI-358507, EBI-25475885;
CC Q13546; U5TQE9: UL39; Xeno; NbExp=3; IntAct=EBI-358507, EBI-11894787;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q60855}. Cell
CC membrane {ECO:0000250|UniProtKB:Q9ZUF4}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13546-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13546-2; Sequence=VSP_037690;
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: The death domain mediates dimerization and activation of its
CC kinase activity during necroptosis and apoptosis (PubMed:29440439). It
CC engages other DD-containing proteins as well as a central
CC (intermediate) region important for NF-kB activation and RHIM-dependent
CC signaling (PubMed:10356400). {ECO:0000269|PubMed:10356400,
CC ECO:0000269|PubMed:29440439}.
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: Proteolytically cleaved by CASP8 at Asp-324 (PubMed:10521396,
CC PubMed:31827281, PubMed:31827280). Cleavage is crucial for limiting
CC TNF-induced apoptosis, necroptosis and inflammatory response
CC (PubMed:31827281, PubMed:31827280). Cleavage abolishes NF-kappa-B
CC activation and enhances the interaction of TRADD with FADD
CC (PubMed:10521396). Proteolytically cleaved by CASP6 during intrinsic
CC apoptosis (PubMed:22858542). {ECO:0000250|UniProtKB:Q60855,
CC ECO:0000269|PubMed:10521396, ECO:0000269|PubMed:31827280,
CC ECO:0000269|PubMed:31827281}.
CC -!- PTM: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation
CC (PubMed:18408713, PubMed:19524513, PubMed:31827280). Phosphorylation of
CC Ser-161 by RIPK3 is necessary for the formation of the necroptosis-
CC inducing complex (PubMed:18408713). Phosphorylation at Ser-25 represses
CC its kinase activity and consequently prevents TNF-mediated RIPK1-
CC dependent cell death (PubMed:30988283). Phosphorylated at Ser-320 by
CC MAP3K7 which requires prior ubiquitination with 'Lys-63'-linked chains
CC by BIRC2/c-IAP1 and BIRC3/c-IAP2 (By similarity). This phosphorylation
CC positively regulates RIPK1 interaction with RIPK3 to promote
CC necroptosis but negatively regulates RIPK1 kinase activity and its
CC interaction with FADD to mediate apoptosis (By similarity).
CC {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:18408713,
CC ECO:0000269|PubMed:19524513, ECO:0000269|PubMed:30988283,
CC ECO:0000269|PubMed:31827280}.
CC -!- PTM: Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-
CC linked type ubiquitin (PubMed:15258597, PubMed:16603398,
CC PubMed:18450452, PubMed:21455173, PubMed:21931591, PubMed:29883609,
CC Ref.34). Polyubiquitination with 'Lys-63'-linked chains by TRAF2
CC induces association with the IKK complex (PubMed:15258597).
CC Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with
CC 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal
CC degradation and consequently down-regulates TNF-alpha-induced NF-kappa-
CC B signaling (PubMed:15258597). 'Lys-48'-linked polyubiquitination by
CC RFFL or RNF34 also promotes proteasomal degradation and negatively
CC regulates TNF-alpha-induced NF-kappa-B signaling (PubMed:18450452,
CC Ref.34). Linear polyubiquitinated; the head-to-tail linear
CC polyubiquitination ('Met-1'-linked) is mediated by the LUBAC complex
CC and decreases protein kinase activity (PubMed:21455173).
CC Deubiquitination of linear polyubiquitin by CYLD promotes the kinase
CC activity (By similarity). Polyubiquitinated with 'Lys-48' and 'Lys-63'-
CC linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation
CC of NF-kappa-B (PubMed:21931591). Ubiquitinated with 'Lys-63'-linked
CC chains by PELI1 (PubMed:29883609). Ubiquitination at Lys-377 with 'Lys-
CC 63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its
CC phosphorylation at Ser-320 mediated by MAP3K7 (By similarity). This
CC ubiquitination is required for NF-kB activation, suppresses RIPK1
CC kinase activity and plays a critical role in preventing cell death
CC during embryonic development (By similarity).
CC {ECO:0000250|UniProtKB:Q60855, ECO:0000269|PubMed:15258597,
CC ECO:0000269|PubMed:16603398, ECO:0000269|PubMed:18450452,
CC ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21931591,
CC ECO:0000269|PubMed:29883609, ECO:0000269|Ref.34}.
CC -!- PTM: (Microbial infection) Glycosylated at Arg-603 by enteropathogenic
CC E.coli protein NleB1: arginine GlcNAcylation prevents
CC homotypic/heterotypic death domain interactions.
CC {ECO:0000305|PubMed:23955153}.
CC -!- DISEASE: Immunodeficiency 57 with autoinflammation (IMD57)
CC [MIM:618108]: An autosomal recessive primary immunodeficiency
CC characterized by lymphopenia and recurrent viral, bacterial, and fungal
CC infections. Patients exhibit early-onset inflammatory bowel disease
CC involving the upper and lower gastrointestinal tract, and develop
CC progressive polyarthritis. {ECO:0000269|PubMed:30026316}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry. RIPK1-deficient immune cells from IMD57 patients have impaired
CC proinflammatory signaling leading to dysregulated cytokine secretion
CC and are prone to necroptosis. {ECO:0000269|PubMed:30026316}.
CC -!- DISEASE: Autoinflammation with episodic fever and lymphadenopathy
CC (AIEFL) [MIM:618852]: An autosomal dominant immunologic disorder
CC characterized by early onset of recurrent episodes of unexplained
CC fever, lymphadenopathy, hepatosplenomegaly, and increased levels of
CC inflammatory cytokines and chemokines in patient serum.
CC {ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAG65471.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/ripk1/";
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DR EMBL; U50062; AAC32232.1; -; mRNA.
DR EMBL; AK314176; BAG36858.1; -; mRNA.
DR EMBL; AK304701; BAG65471.1; ALT_INIT; mRNA.
DR EMBL; AY682848; AAT74626.1; -; Genomic_DNA.
DR EMBL; AL031963; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC126254; AAI26255.1; -; mRNA.
DR EMBL; BC126256; AAI26257.1; -; mRNA.
DR EMBL; AB208926; BAD92163.1; -; mRNA.
DR EMBL; U25994; AAC50137.1; -; mRNA.
DR CCDS; CCDS4482.1; -. [Q13546-1]
DR PIR; T09479; T09479.
DR RefSeq; NP_003795.2; NM_003804.4. [Q13546-1]
DR RefSeq; XP_005249514.2; XM_005249457.3.
DR PDB; 4ITH; X-ray; 2.25 A; A/B=1-294.
DR PDB; 4ITI; X-ray; 2.86 A; A/B=1-294.
DR PDB; 4ITJ; X-ray; 1.80 A; A/B=1-294.
DR PDB; 4NEU; X-ray; 2.57 A; A/B=1-324.
DR PDB; 5HX6; X-ray; 2.23 A; A/B=1-294.
DR PDB; 5TX5; X-ray; 2.56 A; A/B=1-294.
DR PDB; 5V7Z; NMR; -; B/D/F/H=532-549.
DR PDB; 6AC5; X-ray; 1.45 A; A=561-671.
DR PDB; 6C3E; X-ray; 2.60 A; A/B=2-294.
DR PDB; 6C4D; X-ray; 2.52 A; A/B/C/D=2-294.
DR PDB; 6HHO; X-ray; 3.49 A; A/B=1-294.
DR PDB; 6NW2; X-ray; 2.00 A; A/B=1-294.
DR PDB; 6NYH; X-ray; 2.10 A; A/B=1-294.
DR PDB; 6OCQ; X-ray; 2.79 A; A/B=1-294.
DR PDB; 6R5F; X-ray; 3.25 A; A/B/C/D=1-294.
DR PDB; 6RLN; X-ray; 2.87 A; A/B=1-294.
DR PDB; 7CJB; X-ray; 2.80 A; D/H/L/P=189-203.
DR PDB; 7FCZ; X-ray; 2.21 A; A/B=1-294.
DR PDB; 7FD0; X-ray; 2.00 A; A/B=1-294.
DR PDBsum; 4ITH; -.
DR PDBsum; 4ITI; -.
DR PDBsum; 4ITJ; -.
DR PDBsum; 4NEU; -.
DR PDBsum; 5HX6; -.
DR PDBsum; 5TX5; -.
DR PDBsum; 5V7Z; -.
DR PDBsum; 6AC5; -.
DR PDBsum; 6C3E; -.
DR PDBsum; 6C4D; -.
DR PDBsum; 6HHO; -.
DR PDBsum; 6NW2; -.
DR PDBsum; 6NYH; -.
DR PDBsum; 6OCQ; -.
DR PDBsum; 6R5F; -.
DR PDBsum; 6RLN; -.
DR PDBsum; 7CJB; -.
DR PDBsum; 7FCZ; -.
DR PDBsum; 7FD0; -.
DR AlphaFoldDB; Q13546; -.
DR BMRB; Q13546; -.
DR SMR; Q13546; -.
DR BioGRID; 114274; 165.
DR ComplexPortal; CPX-1907; Ripoptosome.
DR CORUM; Q13546; -.
DR DIP; DIP-433N; -.
DR IntAct; Q13546; 93.
DR MINT; Q13546; -.
DR STRING; 9606.ENSP00000259808; -.
DR BindingDB; Q13546; -.
DR ChEMBL; CHEMBL5464; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q13546; -.
DR GuidetoPHARMACOLOGY; 2189; -.
DR GlyGen; Q13546; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q13546; -.
DR MetOSite; Q13546; -.
DR PhosphoSitePlus; Q13546; -.
DR BioMuta; RIPK1; -.
DR DMDM; 60393639; -.
DR CPTAC; CPTAC-1053; -.
DR CPTAC; CPTAC-900; -.
DR CPTAC; CPTAC-901; -.
DR CPTAC; CPTAC-902; -.
DR EPD; Q13546; -.
DR jPOST; Q13546; -.
DR MassIVE; Q13546; -.
DR MaxQB; Q13546; -.
DR PaxDb; Q13546; -.
DR PeptideAtlas; Q13546; -.
DR PRIDE; Q13546; -.
DR ProteomicsDB; 59527; -. [Q13546-1]
DR ProteomicsDB; 59528; -. [Q13546-2]
DR Antibodypedia; 4145; 650 antibodies from 43 providers.
DR DNASU; 8737; -.
DR Ensembl; ENST00000259808.9; ENSP00000259808.3; ENSG00000137275.16. [Q13546-1]
DR Ensembl; ENST00000380409.3; ENSP00000369773.3; ENSG00000137275.16. [Q13546-2]
DR GeneID; 8737; -.
DR KEGG; hsa:8737; -.
DR MANE-Select; ENST00000259808.9; ENSP00000259808.3; NM_001354930.2; NP_001341859.1.
DR UCSC; uc003mux.4; human. [Q13546-1]
DR CTD; 8737; -.
DR DisGeNET; 8737; -.
DR GeneCards; RIPK1; -.
DR HGNC; HGNC:10019; RIPK1.
DR HPA; ENSG00000137275; Low tissue specificity.
DR MalaCards; RIPK1; -.
DR MIM; 603453; gene.
DR MIM; 618108; phenotype.
DR MIM; 618852; phenotype.
DR neXtProt; NX_Q13546; -.
DR OpenTargets; ENSG00000137275; -.
DR Orphanet; 529977; Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome.
DR PharmGKB; PA34394; -.
DR VEuPathDB; HostDB:ENSG00000137275; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000159347; -.
DR HOGENOM; CLU_017229_0_0_1; -.
DR InParanoid; Q13546; -.
DR OrthoDB; 346354at2759; -.
DR PhylomeDB; Q13546; -.
DR TreeFam; TF106506; -.
DR BRENDA; 2.7.10.2; 2681.
DR PathwayCommons; Q13546; -.
DR Reactome; R-HSA-140534; Caspase activation via Death Receptors in the presence of ligand.
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-3371378; Regulation by c-FLIP.
DR Reactome; R-HSA-5213460; RIPK1-mediated regulated necrosis.
DR Reactome; R-HSA-5218900; CASP8 activity is inhibited.
DR Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling.
DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-HSA-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-HSA-5675482; Regulation of necroptotic cell death.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases.
DR Reactome; R-HSA-69416; Dimerization of procaspase-8.
DR Reactome; R-HSA-75893; TNF signaling.
DR Reactome; R-HSA-9013957; TLR3-mediated TICAM1-dependent programmed cell death.
DR Reactome; R-HSA-933543; NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10.
DR Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1.
DR Reactome; R-HSA-9679191; Potential therapeutics for SARS.
DR Reactome; R-HSA-9686347; Microbial modulation of RIPK1-mediated regulated necrosis.
DR Reactome; R-HSA-9693928; Defective RIPK1-mediated regulated necrosis.
DR SignaLink; Q13546; -.
DR SIGNOR; Q13546; -.
DR BioGRID-ORCS; 8737; 35 hits in 1120 CRISPR screens.
DR ChiTaRS; RIPK1; human.
DR GeneWiki; RIPK1; -.
DR GenomeRNAi; 8737; -.
DR Pharos; Q13546; Tchem.
DR PRO; PR:Q13546; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q13546; protein.
DR Bgee; ENSG00000137275; Expressed in granulocyte and 152 other tissues.
DR ExpressionAtlas; Q13546; baseline and differential.
DR Genevisible; Q13546; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031264; C:death-inducing signaling complex; IDA:BHF-UCL.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0043235; C:receptor complex; IDA:BHF-UCL.
DR GO; GO:0097342; C:ripoptosome; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0070513; F:death domain binding; IPI:BHF-UCL.
DR GO; GO:0005123; F:death receptor binding; IPI:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IBA:GO_Central.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
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:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:1990000; P:amyloid fibril formation; IMP:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR GO; GO:0008219; P:cell death; IMP:UniProtKB.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISS:ARUK-UCL.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB.
DR GO; GO:0097527; P:necroptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IEA:Ensembl.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:0060546; P:negative regulation of necroptotic process; ISS:UniProtKB.
DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:1905206; P:positive regulation of hydrogen peroxide-induced cell death; IMP:BHF-UCL.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IDA:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0070105; P:positive regulation of interleukin-6-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB.
DR GO; GO:0045651; P:positive regulation of macrophage differentiation; IMP:UniProtKB.
DR GO; GO:1903800; P:positive regulation of miRNA maturation; IDA:ARUK-UCL.
DR GO; GO:0060545; P:positive regulation of necroptotic process; IMP:UniProtKB.
DR GO; GO:0010940; P:positive regulation of necrotic cell death; IMP:BHF-UCL.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0043068; P:positive regulation of programmed cell death; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; TAS:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:BHF-UCL.
DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0097300; P:programmed necrotic cell death; ISS:ARUK-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB.
DR GO; GO:0070926; P:regulation of ATP:ADP antiporter activity; IMP:BHF-UCL.
DR GO; GO:0034612; P:response to tumor necrosis factor; IMP:BHF-UCL.
DR GO; GO:0097343; P:ripoptosome assembly; IMP:UniProtKB.
DR GO; GO:1901026; P:ripoptosome assembly involved in necroptotic process; IEA:Ensembl.
DR GO; GO:0070231; P:T cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IC:BHF-UCL.
DR CDD; cd08777; Death_RIP1; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR025735; RHIM_dom.
DR InterPro; IPR037934; RIP1_Death.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF12721; RHIM; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 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; Cell membrane;
KW Cytoplasm; Disease variant; Glycoprotein; Host-virus interaction;
KW Inflammatory response; Isopeptide bond; Kinase; Membrane; Necrosis;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1..671
FT /note="Receptor-interacting serine/threonine-protein kinase
FT 1"
FT /id="PRO_0000086606"
FT DOMAIN 17..289
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 583..669
FT /note="Death"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064"
FT REGION 290..582
FT /note="Interaction with SQSTM1"
FT /evidence="ECO:0000269|PubMed:10356400"
FT REGION 331..354
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 389..458
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 531..547
FT /note="RIP homotypic interaction motif (RHIM)"
FT /evidence="ECO:0000269|PubMed:11734559,
FT ECO:0000269|PubMed:29681455"
FT COMPBIAS 331..346
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 403..420
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 423..458
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 138
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 23..31
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 45
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 324..325
FT /note="Cleavage; by CASP8"
FT /evidence="ECO:0000269|PubMed:10521396,
FT ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281"
FT MOD_RES 6
FT /note="Phosphoserine; by IKKA and IKKB"
FT /evidence="ECO:0000269|PubMed:18408713"
FT MOD_RES 20
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000255"
FT MOD_RES 25
FT /note="Phosphoserine; by IKKA and IKKB"
FT /evidence="ECO:0000269|PubMed:18408713,
FT ECO:0000269|PubMed:30988283"
FT MOD_RES 161
FT /note="Phosphoserine; by RIPK3 and autocatalysis"
FT /evidence="ECO:0000255"
FT MOD_RES 166
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:29440439,
FT ECO:0000269|PubMed:31827280"
FT MOD_RES 303
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:18408713"
FT MOD_RES 320
FT /note="Phosphoserine; by MAP3K7"
FT /evidence="ECO:0000269|PubMed:18408713,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163"
FT MOD_RES 331
FT /note="Phosphoserine; by MAP3K7"
FT /evidence="ECO:0000250|UniProtKB:Q60855"
FT MOD_RES 333
FT /note="Phosphoserine; by MAP3K7"
FT /evidence="ECO:0000269|PubMed:18408713"
FT MOD_RES 384
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:15144186"
FT CARBOHYD 603
FT /note="(Microbial infection) N-beta-linked (GlcNAc)
FT arginine"
FT /evidence="ECO:0000269|PubMed:30979585,
FT ECO:0000305|PubMed:23955153, ECO:0007744|PDB:6AC5"
FT CROSSLNK 377
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:16603398"
FT VAR_SEQ 108..153
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_037690"
FT VARIANT 64
FT /note="A -> V (in a colorectal adenocarcinoma sample;
FT somatic mutation; dbSNP:rs774996232)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041039"
FT VARIANT 81
FT /note="V -> I (in a colorectal adenocarcinoma sample;
FT somatic mutation; dbSNP:rs758268804)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041040"
FT VARIANT 220
FT /note="A -> V (in a colorectal adenocarcinoma sample;
FT somatic mutation; dbSNP:rs759012409)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041041"
FT VARIANT 234
FT /note="E -> K (in dbSNP:rs17548383)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_021109"
FT VARIANT 324
FT /note="D -> H (in AIEFL; prevents cleavage by CASP8;
FT increased kinase activity; increased inflammatory
FT response)"
FT /evidence="ECO:0000269|PubMed:31827280,
FT ECO:0000269|PubMed:31827281"
FT /id="VAR_083518"
FT VARIANT 324
FT /note="D -> N (in AIEFL; prevents cleavage by CASP8;
FT changed inflammatory response)"
FT /evidence="ECO:0000269|PubMed:31827281"
FT /id="VAR_083519"
FT VARIANT 324
FT /note="D -> V (in AIEFL; prevents cleavage by CASP8;
FT increased kinase activity; increased inflammatory
FT response)"
FT /evidence="ECO:0000269|PubMed:31827280"
FT /id="VAR_084135"
FT VARIANT 324
FT /note="D -> Y (in AIEFL; prevents cleavage by CASP8;
FT changed inflammatory response)"
FT /evidence="ECO:0000269|PubMed:31827281"
FT /id="VAR_083520"
FT VARIANT 404
FT /note="A -> S (in dbSNP:rs34872409)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041042"
FT VARIANT 438
FT /note="A -> V (in dbSNP:rs3173519)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:7538908, ECO:0000269|PubMed:8612133"
FT /id="VAR_058285"
FT VARIANT 443
FT /note="A -> V (in dbSNP:rs35722193)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041043"
FT VARIANT 569
FT /note="A -> V (in dbSNP:rs55861377)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041044"
FT MUTAGEN 25
FT /note="S->D: Phophomimetic mutant. Significant loss of
FT kinase activity."
FT /evidence="ECO:0000269|PubMed:30988283"
FT MUTAGEN 45
FT /note="K->A: Abolishes kinase activity."
FT /evidence="ECO:0000269|PubMed:30988283,
FT ECO:0000269|PubMed:8612133"
FT MUTAGEN 161
FT /note="S->A: Decreases RIPK1 kinase activity."
FT /evidence="ECO:0000269|PubMed:18408713"
FT MUTAGEN 161
FT /note="S->E: No effect on RIPK1 autophosphorylation."
FT /evidence="ECO:0000269|PubMed:18408713"
FT MUTAGEN 324
FT /note="D->K: Abolishes cleavage by caspase-8."
FT /evidence="ECO:0000269|PubMed:10521396"
FT MUTAGEN 377
FT /note="K->R: Abolishes RIP-mediated NF-Kappa-B activation."
FT /evidence="ECO:0000269|PubMed:16603398"
FT MUTAGEN 536
FT /note="S->C: Strongly reduced homodimerization and
FT interaction with RIPK3."
FT /evidence="ECO:0000269|PubMed:29681455"
FT MUTAGEN 539..542
FT /note="IQIG->AAAA: Abolished cleavage by S.flexneri OspD3."
FT /evidence="ECO:0000269|PubMed:32657447"
FT MUTAGEN 599
FT /note="K->R: Blocks homodimerization, necroptosis and
FT apoptosis."
FT /evidence="ECO:0000269|PubMed:29440439"
FT MUTAGEN 603
FT /note="R->A: Abolished GlcNAcylation by E.coli NleB1."
FT /evidence="ECO:0000269|PubMed:30979585"
FT CONFLICT 258
FT /note="R -> I (in Ref. 3; BAG36858)"
FT /evidence="ECO:0000305"
FT CONFLICT 286
FT /note="R -> S (in Ref. 3; BAG36858)"
FT /evidence="ECO:0000305"
FT CONFLICT 514
FT /note="T -> S (in Ref. 8; AAC50137)"
FT /evidence="ECO:0000305"
FT STRAND 10..12
FT /evidence="ECO:0007829|PDB:7FD0"
FT HELIX 14..16
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 17..19
FT /evidence="ECO:0007829|PDB:5HX6"
FT STRAND 20..22
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 26..28
FT /evidence="ECO:0007829|PDB:7FD0"
FT STRAND 30..36
FT /evidence="ECO:0007829|PDB:4ITJ"
FT TURN 37..39
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 40..51
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 54..56
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 57..68
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 78..84
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 87..93
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 100..104
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 106..108
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 112..131
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 141..143
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 144..146
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 152..154
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 163..168
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 171..173
FT /evidence="ECO:0007829|PDB:4ITH"
FT HELIX 190..192
FT /evidence="ECO:0007829|PDB:6NW2"
FT HELIX 195..197
FT /evidence="ECO:0007829|PDB:4ITJ"
FT STRAND 201..203
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 207..223
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 228..230
FT /evidence="ECO:0007829|PDB:6C4D"
FT HELIX 234..242
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 249..251
FT /evidence="ECO:0007829|PDB:4ITJ"
FT TURN 252..255
FT /evidence="ECO:0007829|PDB:6C3E"
FT HELIX 258..267
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 272..274
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 278..292
FT /evidence="ECO:0007829|PDB:4ITJ"
FT HELIX 294..296
FT /evidence="ECO:0007829|PDB:4NEU"
FT HELIX 297..309
FT /evidence="ECO:0007829|PDB:4NEU"
FT TURN 310..312
FT /evidence="ECO:0007829|PDB:4NEU"
FT STRAND 533..542
FT /evidence="ECO:0007829|PDB:5V7Z"
FT HELIX 575..577
FT /evidence="ECO:0007829|PDB:6AC5"
FT HELIX 584..593
FT /evidence="ECO:0007829|PDB:6AC5"
FT HELIX 599..604
FT /evidence="ECO:0007829|PDB:6AC5"
FT HELIX 609..618
FT /evidence="ECO:0007829|PDB:6AC5"
FT TURN 619..622
FT /evidence="ECO:0007829|PDB:6AC5"
FT HELIX 624..643
FT /evidence="ECO:0007829|PDB:6AC5"
FT HELIX 646..655
FT /evidence="ECO:0007829|PDB:6AC5"
FT HELIX 659..668
FT /evidence="ECO:0007829|PDB:6AC5"
SQ SEQUENCE 671 AA; 75931 MW; 976E2428D525A9B2 CRC64;
MQPDMSLNVI KMKSSDFLES AELDSGGFGK VSLCFHRTQG LMIMKTVYKG PNCIEHNEAL
LEEAKMMNRL RHSRVVKLLG VIIEEGKYSL VMEYMEKGNL MHVLKAEMST PLSVKGRIIL
EIIEGMCYLH GKGVIHKDLK PENILVDNDF HIKIADLGLA SFKMWSKLNN EEHNELREVD
GTAKKNGGTL YYMAPEHLND VNAKPTEKSD VYSFAVVLWA IFANKEPYEN AICEQQLIMC
IKSGNRPDVD DITEYCPREI ISLMKLCWEA NPEARPTFPG IEEKFRPFYL SQLEESVEED
VKSLKKEYSN ENAVVKRMQS LQLDCVAVPS SRSNSATEQP GSLHSSQGLG MGPVEESWFA
PSLEHPQEEN EPSLQSKLQD EANYHLYGSR MDRQTKQQPR QNVAYNREEE RRRRVSHDPF
AQQRPYENFQ NTEGKGTAYS SAASHGNAVH QPSGLTSQPQ VLYQNNGLYS SHGFGTRPLD
PGTAGPRVWY RPIPSHMPSL HNIPVPETNY LGNTPTMPFS SLPPTDESIK YTIYNSTGIQ
IGAYNYMEIG GTSSSLLDST NTNFKEEPAA KYQAIFDNTT SLTDKHLDPI RENLGKHWKN
CARKLGFTQS QIDEIDHDYE RDGLKEKVYQ MLQKWVMREG IKGATVGKLA QALHQCSRID
LLSSLIYVSQ N
