MLKL_HUMAN
ID MLKL_HUMAN Reviewed; 471 AA.
AC Q8NB16; A6NCE4; Q8N6V0;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 168.
DE RecName: Full=Mixed lineage kinase domain-like protein {ECO:0000305};
DE Short=hMLKL {ECO:0000303|PubMed:12471243};
GN Name=MLKL {ECO:0000303|PubMed:22265413, ECO:0000312|HGNC:HGNC:26617};
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] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND NOMENCLATURE.
RX PubMed=12471243; DOI=10.1126/science.1075762;
RA Manning G., Whyte D.B., Martinez R., Hunter T., Sudarsanam S.;
RT "The protein kinase complement of the human genome.";
RL Science 298:1912-1934(2002).
RN [2] {ECO:0000305, ECO:0000312|EMBL:BAC03728.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Chondrocyte {ECO:0000312|EMBL:BAC03728.1};
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [4] {ECO:0000305, ECO:0000312|EMBL:AAH28141.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Leukocyte {ECO:0000312|EMBL:AAH28141.1};
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 [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-125, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-125, 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 [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [9]
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 [10]
RP FUNCTION, INTERACTION WITH RIPK3, ACTIVITY REGULATION, PHOSPHORYLATION AT
RP THR-357 AND SER-358, AND MUTAGENESIS OF CYS-86; THR-357 AND SER-358.
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 [11]
RP FUNCTION, AND IDENTIFICATION IN COMPLEX WITH PGAM5; RIPK1 AND RIPK3.
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 [12]
RP FUNCTION, AND INTERACTION WITH RIPK3.
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 [13]
RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, AND MUTAGENESIS OF LEU-58; ILE-76;
RP LEU-162 AND LEU-165.
RX PubMed=24316671; DOI=10.1038/ncb2883;
RA Cai Z., Jitkaew S., Zhao J., Chiang H.C., Choksi S., Liu J., Ward Y.,
RA Wu L.G., Liu Z.G.;
RT "Plasma membrane translocation of trimerized MLKL protein is required for
RT TNF-induced necroptosis.";
RL Nat. Cell Biol. 16:55-65(2014).
RN [14]
RP INTERACTION WITH RIPK3.
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 [15]
RP FUNCTION, ACTIVITY REGULATION, PHOSPHORYLATION AT SER-358, SUBUNIT, REGION
RP NBB, AND SUBCELLULAR LOCATION.
RX PubMed=29883610; DOI=10.1016/j.molcel.2018.05.010;
RA Dovey C.M., Diep J., Clarke B.P., Hale A.T., McNamara D.E., Guo H.,
RA Brown N.W. Jr., Cao J.Y., Grace C.R., Gough P.J., Bertin J., Dixon S.J.,
RA Fiedler D., Mocarski E.S., Kaiser W.J., Moldoveanu T., York J.D.,
RA Carette J.E.;
RT "MLKL requires the inositol phosphate code to execute necroptosis.";
RL Mol. Cell 70:936-948(2018).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 189-471, ATP-BINDING, AND
RP MUTAGENESIS OF LYS-230; LYS-331 AND GLU-351.
RX PubMed=24219132; DOI=10.1042/bj20131270;
RA Murphy J.M., Lucet I.S., Hildebrand J.M., Tanzer M.C., Young S.N.,
RA Sharma P., Lessene G., Alexander W.S., Babon J.J., Silke J., Czabotar P.E.;
RT "Insights into the evolution of divergent nucleotide-binding mechanisms
RT among pseudokinases revealed by crystal structures of human and mouse
RT MLKL.";
RL Biochem. J. 457:369-377(2014).
RN [17]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 179-471.
RX PubMed=24095729; DOI=10.1016/j.celrep.2013.08.044;
RA Xie T., Peng W., Yan C., Wu J., Gong X., Shi Y.;
RT "Structural insights into RIP3-mediated necroptotic signaling.";
RL Cell Rep. 5:70-78(2013).
RN [18]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-52; GLU-100; PRO-132; GLN-146; LEU-169;
RP PRO-291; MET-364; ILE-398 AND HIS-421.
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).
CC -!- FUNCTION: Pseudokinase that plays a key role in TNF-induced
CC necroptosis, a programmed cell death process (PubMed:22265413,
CC PubMed:22265414, PubMed:22421439, PubMed:24316671). Does not have
CC protein kinase activity (PubMed:22265413, PubMed:22265414,
CC PubMed:22421439, PubMed:24316671). Activated following phosphorylation
CC by RIPK3, leading to homotrimerization, localization to the plasma
CC membrane and execution of programmed necrosis characterized by calcium
CC influx and plasma membrane damage (PubMed:22265413, PubMed:22265414,
CC PubMed:22421439, PubMed:24316671). In addition to TNF-induced
CC necroptosis, necroptosis can also take place in the nucleus in response
CC to orthomyxoviruses infection: following activation by ZBP1, MLKL is
CC phosphorylated by RIPK3 in the nucleus, triggering disruption of the
CC nuclear envelope and leakage of cellular DNA into the cytosol.following
CC ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear
CC RIPK3 catalyzes phosphorylation and activation of MLKL, promoting
CC disruption of the nuclear envelope and leakage of cellular DNA into the
CC cytosol (By similarity). Binds to highly phosphorylated inositol
CC phosphates such as inositolhexakisphosphate (InsP6) which is essential
CC for its necroptotic function (PubMed:29883610).
CC {ECO:0000250|UniProtKB:Q9D2Y4, ECO:0000269|PubMed:22265413,
CC ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439,
CC ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883610}.
CC -!- ACTIVITY REGULATION: Activated via binding to highly phosphorylated
CC inositol phosphates such as inositolhexakisphosphate (InsP6) which
CC mediates the release of an N-terminal auto-inhibitory region
CC (PubMed:29883610). Activation requires not only RIPK3-dependent
CC phosphorylation but also binding to highly phosphorylated inositol
CC phosphates (PubMed:29883610). Inhibited by necrosulfonamide, a specific
CC inhibitor of necroptosis that targets Cys-86 (PubMed:22265413).
CC {ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:29883610}.
CC -!- SUBUNIT: Homooligomer (PubMed:29883610). Homotrimer; forms homotrimers
CC on necroptosis induction (PubMed:24316671). Upon TNF-induced necrosis,
CC forms in complex with PGAM5, RIPK1 and RIPK3 (PubMed:22265414). Within
CC this complex, may play a role in the proper targeting of RIPK1-RIPK3 to
CC its downstream effector PGAM5 (PubMed:22265414). Interacts with RIPK3;
CC the interaction is direct and promotes its phosphorylation and
CC subsequent activation (PubMed:22265413, PubMed:22421439,
CC PubMed:29883609). {ECO:0000269|PubMed:22265413,
CC ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439,
CC ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883609,
CC ECO:0000269|PubMed:29883610}.
CC -!- INTERACTION:
CC Q8NB16; Q9Y572: RIPK3; NbExp=10; IntAct=EBI-1055040, EBI-298250;
CC Q8NB16-1; Q8NB16-1: MLKL; NbExp=2; IntAct=EBI-16084674, EBI-16084674;
CC Q8NB16-2; P20618: PSMB1; NbExp=3; IntAct=EBI-19046912, EBI-372273;
CC Q8NB16-2; P60903: S100A10; NbExp=3; IntAct=EBI-19046912, EBI-717048;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24316671}. Cell
CC membrane {ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883610}.
CC Nucleus {ECO:0000250|UniProtKB:Q9D2Y4}. Note=Localizes to the cytoplasm
CC and translocates to the plasma membrane on necroptosis induction
CC (PubMed:24316671). Localizes to the nucleus in response to
CC orthomyxoviruses infection (By similarity).
CC {ECO:0000250|UniProtKB:Q9D2Y4, ECO:0000269|PubMed:24316671}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1 {ECO:0000303|PubMed:12471243, ECO:0000303|PubMed:14702039};
CC IsoId=Q8NB16-1; Sequence=Displayed;
CC Name=2 {ECO:0000303|PubMed:15489334};
CC IsoId=Q8NB16-2; Sequence=VSP_052133, VSP_052134;
CC -!- DOMAIN: The protein kinase domain is catalytically inactive but
CC contains an unusual pseudoactive site with an interaction between Lys-
CC 230 and Gln-356 residues (By similarity). Upon phosphorylation by
CC RIPK3, undergoes an active conformation (By similarity).
CC {ECO:0000250|UniProtKB:Q9D2Y4}.
CC -!- DOMAIN: The coiled coil region 2 is responsible for homotrimerization.
CC {ECO:0000269|PubMed:24316671}.
CC -!- PTM: Phosphorylation by RIPK3 induces a conformational switch that is
CC required for necroptosis (PubMed:22265413). It also induces
CC homotrimerization and localization to the plasma membrane
CC (PubMed:22265413). {ECO:0000269|PubMed:22265413}.
CC -!- MISCELLANEOUS: Interaction with RIPK3 is species specific: human MLKL
CC only interacts with human RIPK3 and not mouse RIPK3.
CC {ECO:0000305|PubMed:22265413}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. {ECO:0000305}.
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DR EMBL; AK091708; BAC03728.1; -; mRNA.
DR EMBL; AC109599; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC028141; AAH28141.1; -; mRNA.
DR CCDS; CCDS32487.1; -. [Q8NB16-1]
DR CCDS; CCDS45528.1; -. [Q8NB16-2]
DR RefSeq; NP_001135969.1; NM_001142497.2. [Q8NB16-2]
DR RefSeq; NP_689862.1; NM_152649.3. [Q8NB16-1]
DR RefSeq; XP_005255891.1; XM_005255834.3. [Q8NB16-1]
DR PDB; 2MSV; NMR; -; A=1-154.
DR PDB; 4M67; X-ray; 1.90 A; A=179-471.
DR PDB; 4MWI; X-ray; 1.70 A; A=183-471.
DR PDB; 5KNJ; X-ray; 2.88 A; A/B=191-471.
DR PDB; 5KO1; X-ray; 2.16 A; A=191-471.
DR PDB; 6BWK; X-ray; 2.79 A; A=190-471.
DR PDB; 6D74; NMR; -; A=1-156.
DR PDB; 6LK5; X-ray; 2.50 A; A=1-471.
DR PDB; 6LK6; X-ray; 2.41 A; A=179-471.
DR PDB; 6O5Z; X-ray; 2.29 A; A/B=190-471.
DR PDB; 6UX8; X-ray; 2.50 A; A=5-154.
DR PDB; 6ZLE; NMR; -; A=2-154.
DR PDB; 6ZPR; NMR; -; A=2-154.
DR PDB; 6ZVO; X-ray; 1.37 A; A/B/C=2-150.
DR PDB; 6ZZ1; X-ray; 1.64 A; A/B=2-150.
DR PDB; 7JW7; X-ray; 2.63 A; A=190-471.
DR PDB; 7JXU; X-ray; 2.44 A; A/B=190-471.
DR PDB; 7MON; X-ray; 2.23 A; A=190-471.
DR PDB; 7NM2; NMR; -; A=2-154.
DR PDB; 7NM4; NMR; -; A=2-154.
DR PDB; 7NM5; NMR; -; A=2-154.
DR PDBsum; 2MSV; -.
DR PDBsum; 4M67; -.
DR PDBsum; 4MWI; -.
DR PDBsum; 5KNJ; -.
DR PDBsum; 5KO1; -.
DR PDBsum; 6BWK; -.
DR PDBsum; 6D74; -.
DR PDBsum; 6LK5; -.
DR PDBsum; 6LK6; -.
DR PDBsum; 6O5Z; -.
DR PDBsum; 6UX8; -.
DR PDBsum; 6ZLE; -.
DR PDBsum; 6ZPR; -.
DR PDBsum; 6ZVO; -.
DR PDBsum; 6ZZ1; -.
DR PDBsum; 7JW7; -.
DR PDBsum; 7JXU; -.
DR PDBsum; 7MON; -.
DR PDBsum; 7NM2; -.
DR PDBsum; 7NM4; -.
DR PDBsum; 7NM5; -.
DR AlphaFoldDB; Q8NB16; -.
DR BMRB; Q8NB16; -.
DR SMR; Q8NB16; -.
DR BioGRID; 128244; 32.
DR DIP; DIP-41782N; -.
DR IntAct; Q8NB16; 21.
DR MINT; Q8NB16; -.
DR STRING; 9606.ENSP00000308351; -.
DR BindingDB; Q8NB16; -.
DR ChEMBL; CHEMBL1938217; -.
DR GuidetoPHARMACOLOGY; 2106; -.
DR TCDB; 1.A.105.1.1; the mixed lineage kinase domain-like (mlkl) family.
DR GlyGen; Q8NB16; 4 sites, 1 O-linked glycan (4 sites).
DR iPTMnet; Q8NB16; -.
DR PhosphoSitePlus; Q8NB16; -.
DR BioMuta; MLKL; -.
DR DMDM; 74762545; -.
DR CPTAC; CPTAC-895; -.
DR CPTAC; CPTAC-896; -.
DR EPD; Q8NB16; -.
DR jPOST; Q8NB16; -.
DR MassIVE; Q8NB16; -.
DR MaxQB; Q8NB16; -.
DR PaxDb; Q8NB16; -.
DR PeptideAtlas; Q8NB16; -.
DR PRIDE; Q8NB16; -.
DR ProteomicsDB; 72718; -. [Q8NB16-1]
DR ProteomicsDB; 72719; -. [Q8NB16-2]
DR Antibodypedia; 2097; 366 antibodies from 38 providers.
DR DNASU; 197259; -.
DR Ensembl; ENST00000306247.11; ENSP00000303118.7; ENSG00000168404.13. [Q8NB16-2]
DR Ensembl; ENST00000308807.12; ENSP00000308351.7; ENSG00000168404.13. [Q8NB16-1]
DR GeneID; 197259; -.
DR KEGG; hsa:197259; -.
DR MANE-Select; ENST00000308807.12; ENSP00000308351.7; NM_152649.4; NP_689862.1.
DR UCSC; uc002fdb.3; human. [Q8NB16-1]
DR CTD; 197259; -.
DR DisGeNET; 197259; -.
DR GeneCards; MLKL; -.
DR HGNC; HGNC:26617; MLKL.
DR HPA; ENSG00000168404; Low tissue specificity.
DR MIM; 615153; gene.
DR neXtProt; NX_Q8NB16; -.
DR OpenTargets; ENSG00000168404; -.
DR PharmGKB; PA142671349; -.
DR VEuPathDB; HostDB:ENSG00000168404; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00390000016453; -.
DR HOGENOM; CLU_044216_0_0_1; -.
DR InParanoid; Q8NB16; -.
DR OMA; ESKVDWM; -.
DR OrthoDB; 1388260at2759; -.
DR PhylomeDB; Q8NB16; -.
DR TreeFam; TF328453; -.
DR PathwayCommons; Q8NB16; -.
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-9686347; Microbial modulation of RIPK1-mediated regulated necrosis.
DR SignaLink; Q8NB16; -.
DR SIGNOR; Q8NB16; -.
DR BioGRID-ORCS; 197259; 15 hits in 1114 CRISPR screens.
DR ChiTaRS; MLKL; human.
DR GenomeRNAi; 197259; -.
DR Pharos; Q8NB16; Tchem.
DR PRO; PR:Q8NB16; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q8NB16; protein.
DR Bgee; ENSG00000168404; Expressed in granulocyte and 164 other tissues.
DR ExpressionAtlas; Q8NB16; baseline and differential.
DR Genevisible; Q8NB16; HS.
DR GO; GO:0030054; C:cell junction; IDA:HPA.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:InterPro.
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:0070266; P:necroptotic process; IMP:UniProtKB.
DR GO; GO:0097527; P:necroptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0070207; P:protein homotrimerization; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR Gene3D; 1.20.930.20; -; 1.
DR InterPro; IPR036537; Adaptor_Cbl_N_dom_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane;
KW Coiled coil; Cytoplasm; Membrane; Necrosis; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..471
FT /note="Mixed lineage kinase domain-like protein"
FT /id="PRO_0000248239"
FT DOMAIN 194..469
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..149
FT /note="N-terminal bundle and brace (NBB); mediates INSP6
FT binding"
FT /evidence="ECO:0000269|PubMed:29883610"
FT COILED 55..84
FT /evidence="ECO:0000255"
FT COILED 139..180
FT /evidence="ECO:0000255"
FT BINDING 209..217
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 230
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT SITE 86
FT /note="Target of necrosulfonamide inhibitor"
FT /evidence="ECO:0000269|PubMed:22265413"
FT MOD_RES 125
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976"
FT MOD_RES 357
FT /note="Phosphothreonine; by RIPK3"
FT /evidence="ECO:0000269|PubMed:22265413"
FT MOD_RES 358
FT /note="Phosphoserine; by RIPK3"
FT /evidence="ECO:0000269|PubMed:22265413,
FT ECO:0000269|PubMed:29883610"
FT MOD_RES 360
FT /note="Phosphoserine; by RIPK3"
FT /evidence="ECO:0000250|UniProtKB:Q9D2Y4"
FT VAR_SEQ 179..205
FT /note="YLPPKCMQEIPQEQIKEIKKEQLSGSP -> SLESSSGKSPLEISRFKVKNV
FT KTGSAS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_052133"
FT VAR_SEQ 206..413
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_052134"
FT VARIANT 52
FT /note="S -> T (in dbSNP:rs34251827)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041350"
FT VARIANT 100
FT /note="D -> E (in dbSNP:rs33987771)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041351"
FT VARIANT 132
FT /note="S -> P (in dbSNP:rs35589326)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041352"
FT VARIANT 146
FT /note="R -> Q (in dbSNP:rs34515646)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041353"
FT VARIANT 169
FT /note="M -> L (in dbSNP:rs55929310)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041354"
FT VARIANT 291
FT /note="L -> P (in a gastric adenocarcinoma sample; somatic
FT mutation; dbSNP:rs1313508921)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041355"
FT VARIANT 364
FT /note="T -> M (in dbSNP:rs34389205)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041356"
FT VARIANT 398
FT /note="F -> I (in a gastric adenocarcinoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041357"
FT VARIANT 421
FT /note="R -> H (in dbSNP:rs55987292)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041358"
FT MUTAGEN 58
FT /note="L->G: Does not affect formation of homotrimers,
FT while translocation to the plasma membrane on necroptosis
FT induction is impaired; when associated with G-76."
FT /evidence="ECO:0000269|PubMed:24316671"
FT MUTAGEN 76
FT /note="I->G: Does not affect formation of homotrimers,
FT while translocation to the plasma membrane on necroptosis
FT induction is impaired; when associated with G-58."
FT /evidence="ECO:0000269|PubMed:24316671"
FT MUTAGEN 86
FT /note="C->S: Abolishes binding to necrosulfonamide
FT inhibitor."
FT /evidence="ECO:0000269|PubMed:22265413"
FT MUTAGEN 162
FT /note="L->G: Impairs formation of homotrimers and
FT translocation to the plasma membrane on necroptosis
FT induction; when associated with G-165."
FT /evidence="ECO:0000269|PubMed:24316671"
FT MUTAGEN 165
FT /note="L->G: Impairs formation of homotrimers and
FT translocation to the plasma membrane on necroptosis
FT induction; when associated with G-162."
FT /evidence="ECO:0000269|PubMed:24316671"
FT MUTAGEN 230
FT /note="K->M: Abolishes ATP-binding."
FT /evidence="ECO:0000269|PubMed:24219132"
FT MUTAGEN 331
FT /note="K->N: Impairs ATP-binding."
FT /evidence="ECO:0000269|PubMed:24219132"
FT MUTAGEN 351
FT /note="E->K: Binds ATP with an enhanced affinity."
FT /evidence="ECO:0000269|PubMed:24219132"
FT MUTAGEN 357..358
FT /note="TS->ED: Mimics phosphorylation state; acts as a
FT dominant-negative mutant that impairs necroptosis."
FT MUTAGEN 357
FT /note="T->A: No effect. Abolishes ability to mediate
FT necroptosis; when associated with A-358."
FT /evidence="ECO:0000269|PubMed:22265413"
FT MUTAGEN 358
FT /note="S->A: No effect. Abolishes ability to mediate
FT necroptosis; when associated with A-357."
FT /evidence="ECO:0000269|PubMed:22265413"
FT HELIX 2..20
FT /evidence="ECO:0007829|PDB:6ZVO"
FT STRAND 22..24
FT /evidence="ECO:0007829|PDB:6ZZ1"
FT HELIX 25..46
FT /evidence="ECO:0007829|PDB:6ZVO"
FT HELIX 56..79
FT /evidence="ECO:0007829|PDB:6ZVO"
FT HELIX 82..90
FT /evidence="ECO:0007829|PDB:6ZVO"
FT STRAND 93..96
FT /evidence="ECO:0007829|PDB:2MSV"
FT HELIX 99..120
FT /evidence="ECO:0007829|PDB:6ZVO"
FT TURN 128..132
FT /evidence="ECO:0007829|PDB:2MSV"
FT HELIX 133..148
FT /evidence="ECO:0007829|PDB:6ZVO"
FT HELIX 198..201
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 202..204
FT /evidence="ECO:0007829|PDB:6O5Z"
FT STRAND 207..211
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 213..222
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 225..232
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 240..256
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 265..271
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 274..276
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 278..284
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 291..297
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 303..322
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 323..325
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 334..336
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 337..339
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 345..347
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 349..352
FT /evidence="ECO:0007829|PDB:7MON"
FT HELIX 353..359
FT /evidence="ECO:0007829|PDB:7MON"
FT TURN 360..362
FT /evidence="ECO:0007829|PDB:7JXU"
FT HELIX 373..376
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 379..383
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 391..407
FT /evidence="ECO:0007829|PDB:4MWI"
FT TURN 411..414
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 417..425
FT /evidence="ECO:0007829|PDB:4MWI"
FT STRAND 435..437
FT /evidence="ECO:0007829|PDB:6O5Z"
FT HELIX 439..448
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 453..455
FT /evidence="ECO:0007829|PDB:4MWI"
FT HELIX 459..467
FT /evidence="ECO:0007829|PDB:4MWI"
SQ SEQUENCE 471 AA; 54479 MW; 005E7F7AB6D20649 CRC64;
MENLKHIITL GQVIHKRCEE MKYCKKQCRR LGHRVLGLIK PLEMLQDQGK RSVPSEKLTT
AMNRFKAALE EANGEIEKFS NRSNICRFLT ASQDKILFKD VNRKLSDVWK ELSLLLQVEQ
RMPVSPISQG ASWAQEDQQD ADEDRRAFQM LRRDNEKIEA SLRRLEINMK EIKETLRQYL
PPKCMQEIPQ EQIKEIKKEQ LSGSPWILLR ENEVSTLYKG EYHRAPVAIK VFKKLQAGSI
AIVRQTFNKE IKTMKKFESP NILRIFGICI DETVTPPQFS IVMEYCELGT LRELLDREKD
LTLGKRMVLV LGAARGLYRL HHSEAPELHG KIRSSNFLVT QGYQVKLAGF ELRKTQTSMS
LGTTREKTDR VKSTAYLSPQ ELEDVFYQYD VKSEIYSFGI VLWEIATGDI PFQGCNSEKI
RKLVAVKRQQ EPLGEDCPSE LREIIDECRA HDPSVRPSVD EILKKLSTFS K
