MLKL_MOUSE
ID MLKL_MOUSE Reviewed; 472 AA.
AC Q9D2Y4; Q8CIJ5;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Mixed lineage kinase domain-like protein {ECO:0000305};
GN Name=Mlkl {ECO:0000303|PubMed:23835476, ECO:0000312|MGI:MGI:1921818};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1] {ECO:0000305, ECO:0000312|EMBL:BAE41668.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:BAB31320.1}, and
RC NOD {ECO:0000312|EMBL:BAE41668.1};
RC TISSUE=Cecum {ECO:0000312|EMBL:BAB31320.1}, and
RC Dendritic cell {ECO:0000312|EMBL:BAE41668.1};
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2] {ECO:0000305, ECO:0000312|EMBL:AAH23755.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=FVB/N {ECO:0000312|EMBL:AAH23755.1};
RC TISSUE=Mammary gland {ECO:0000312|EMBL:AAH23755.1};
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 [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Heart, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [4]
RP INTERACTION WITH RIPK3.
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 [5]
RP TISSUE SPECIFICITY, DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=23835476; DOI=10.1038/cr.2013.91;
RA Wu J., Huang Z., Ren J., Zhang Z., He P., Li Y., Ma J., Chen W., Zhang Y.,
RA Zhou X., Yang Z., Wu S.Q., Chen L., Han J.;
RT "Mlkl knockout mice demonstrate the indispensable role of Mlkl in
RT necroptosis.";
RL Cell Res. 23:994-1006(2013).
RN [6]
RP FUNCTION.
RX PubMed=24019532; DOI=10.1074/jbc.m113.462341;
RA Kaiser W.J., Sridharan H., Huang C., Mandal P., Upton J.W., Gough P.J.,
RA Sehon C.A., Marquis R.W., Bertin J., Mocarski E.S.;
RT "Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL.";
RL J. Biol. Chem. 288:31268-31279(2013).
RN [7]
RP INTERACTION WITH RIPK3.
RX PubMed=23612963; DOI=10.1074/jbc.m112.435545;
RA Chen W., Zhou Z., Li L., Zhong C.Q., Zheng X., Wu X., Zhang Y., Ma H.,
RA Huang D., Li W., Xia Z., Han J.;
RT "Diverse sequence determinants control human and mouse receptor interacting
RT protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in
RT necroptotic signaling.";
RL J. Biol. Chem. 288:16247-16261(2013).
RN [8]
RP FUNCTION, INTERACTION WITH RIPK3, AND DISRUPTION PHENOTYPE.
RX PubMed=27321907; DOI=10.1016/j.chom.2016.05.011;
RA Nogusa S., Thapa R.J., Dillon C.P., Liedmann S., Oguin T.H. III,
RA Ingram J.P., Rodriguez D.A., Kosoff R., Sharma S., Sturm O., Verbist K.,
RA Gough P.J., Bertin J., Hartmann B.M., Sealfon S.C., Kaiser W.J.,
RA Mocarski E.S., Lopez C.B., Thomas P.G., Oberst A., Green D.R.,
RA Balachandran S.;
RT "RIPK3 activates parallel pathways of MLKL-driven necroptosis and FADD-
RT mediated apoptosis to protect against influenza A virus.";
RL Cell Host Microbe 20:13-24(2016).
RN [9]
RP DISRUPTION PHENOTYPE.
RX PubMed=27819681; DOI=10.1038/nature20558;
RA Lin J., Kumari S., Kim C., Van T.M., Wachsmuth L., Polykratis A.,
RA Pasparakis M.;
RT "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation.";
RL Nature 540:124-128(2016).
RN [10]
RP FUNCTION, PHOSPHORYLATION BY RIPK3, SUBCELLULAR LOCATION, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=32200799; DOI=10.1016/j.cell.2020.02.050;
RA Zhang T., Yin C., Boyd D.F., Quarato G., Ingram J.P., Shubina M.,
RA Ragan K.B., Ishizuka T., Crawford J.C., Tummers B., Rodriguez D.A., Xue J.,
RA Peri S., Kaiser W.J., Lopez C.B., Xu Y., Upton J.W., Thomas P.G.,
RA Green D.R., Balachandran S.;
RT "Influenza virus Z-RNAs induce ZBP1-mediated necroptosis.";
RL Cell 180:1115-1129(2020).
RN [11]
RP FUNCTION, PHOSPHORYLATION BY RIPK3, AND SUBCELLULAR LOCATION.
RX PubMed=32296175; DOI=10.1038/s41586-020-2129-8;
RA Jiao H., Wachsmuth L., Kumari S., Schwarzer R., Lin J., Eren R.O.,
RA Fisher A., Lane R., Young G.R., Kassiotis G., Kaiser W.J., Pasparakis M.;
RT "Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and
RT inflammation.";
RL Nature 580:391-395(2020).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 182-472 IN COMPLEX WITH RIPK3,
RP INTERACTION WITH RIPK3, PHOSPHORYLATION AT SER-345; SER-347; THR-349 AND
RP SER-352, AND MUTAGENESIS OF SER-404 AND 404-SER-LYS-405.
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 [13]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS), ATP-BINDING, INTERACTION WITH RIPK3,
RP PHOSPHORYLATION AT SER-345; SER-347 AND THR-349, MUTAGENESIS OF LYS-219;
RP GLU-239; LEU-280; GLN-343; SER-345 AND PHE-385, DISRUPTION PHENOTYPE, AND
RP FUNCTION.
RX PubMed=24012422;
RA Murphy J.M., Czabotar P.E., Hildebrand J.M., Lucet I.S., Zhang J.G.,
RA Alvarez-Diaz S., Lewis R., Lalaoui N., Metcalf D., Webb A.I., Young S.N.,
RA Varghese L.N., Tannahill G.M., Hatchell E.C., Majewski I.J., Okamoto T.,
RA Dobson R.C., Hilton D.J., Babon J.J., Nicola N.A., Strasser A., Silke J.,
RA Alexander W.S.;
RT "The pseudokinase MLKL mediates necroptosis via a molecular switch
RT mechanism.";
RL Immunity 39:443-453(2013).
CC -!- FUNCTION: Pseudokinase that plays a key role in TNF-induced
CC necroptosis, a programmed cell death process (PubMed:23835476,
CC PubMed:27321907, PubMed:24012422, PubMed:24019532, PubMed:32200799,
CC PubMed:32296175). Does not have protein kinase activity
CC (PubMed:24012422). Activated following phosphorylation by RIPK3,
CC leading to homotrimerization, localization to the plasma membrane and
CC execution of programmed necrosis characterized by calcium influx and
CC plasma membrane damage (PubMed:23835476, PubMed:27321907,
CC PubMed:24012422, PubMed:24019532). In addition to TNF-induced
CC necroptosis, necroptosis can also take place in the nucleus in response
CC to orthomyxoviruses infection: following ZBP1 activation, which senses
CC double-stranded Z-RNA structures, nuclear RIPK3 catalyzes
CC phosphorylation and activation of MLKL, promoting disruption of the
CC nuclear envelope and leakage of cellular DNA into the cytosol
CC (PubMed:32200799, PubMed:32296175). Binds to highly phosphorylated
CC inositol phosphates such as inositolhexakisphosphate (InsP6) which is
CC essential for its necroptotic function (By similarity).
CC {ECO:0000250|UniProtKB:Q8NB16, ECO:0000269|PubMed:23835476,
CC ECO:0000269|PubMed:24012422, ECO:0000269|PubMed:24019532,
CC ECO:0000269|PubMed:27321907, ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175}.
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 (By
CC similarity). Activation requires not only RIPK3-dependent
CC phosphorylation but also binding to highly phosphorylated inositol
CC phosphates (By similarity). {ECO:0000250|UniProtKB:Q8NB16}.
CC -!- SUBUNIT: Homooligomer (By similarity). Homotrimer; forms homotrimers on
CC necroptosis induction (By similarity). Upon TNF-induced necrosis, forms
CC in complex with PGAM5, RIPK1 and RIPK3 (By similarity). Within this
CC complex, may play a role in the proper targeting of RIPK1-RIPK3 to its
CC downstream effector PGAM5 (By similarity). Interacts with RIPK3; the
CC interaction is direct and promotes its phosphorylation and subsequent
CC activation (PubMed:22265413, PubMed:23612963, PubMed:27321907,
CC PubMed:24012422, PubMed:24095729). {ECO:0000250|UniProtKB:Q8NB16,
CC ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:23612963,
CC ECO:0000269|PubMed:24012422, ECO:0000269|PubMed:24095729,
CC ECO:0000269|PubMed:27321907}.
CC -!- INTERACTION:
CC Q9D2Y4; Q9QZL0: Ripk3; NbExp=3; IntAct=EBI-5401970, EBI-2367423;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175}. Cell membrane
CC {ECO:0000269|PubMed:32200799}. Nucleus {ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175}. Note=Localizes to the cytoplasm and
CC translocates to the plasma membrane on necroptosis induction (By
CC similarity). Localizes to the nucleus in response to orthomyxoviruses
CC infection (PubMed:32200799). {ECO:0000250|UniProtKB:Q8NB16,
CC ECO:0000269|PubMed:32200799}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1 {ECO:0000303|PubMed:16141072};
CC IsoId=Q9D2Y4-1; Sequence=Displayed;
CC Name=2 {ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:16141072};
CC IsoId=Q9D2Y4-2; Sequence=VSP_052132;
CC -!- TISSUE SPECIFICITY: Highly expressed in thymus, colon, intestine,
CC liver, spleen and lung. Expressed at much lower level in skeletal
CC muscle, heart and kidney. Not detected in brain.
CC {ECO:0000269|PubMed:23835476}.
CC -!- DOMAIN: The coiled coil region 2 is responsible for homotrimerization.
CC {ECO:0000250|UniProtKB:Q8NB16}.
CC -!- DOMAIN: The protein kinase domain is catalytically inactive but
CC contains an unusual pseudoactive site with an interaction between Lys-
CC 219 and Gln-343 residues (PubMed:24012422, PubMed:24095729). Upon
CC phosphorylation by RIPK3, undergoes an active conformation
CC (PubMed:24012422, PubMed:24095729). {ECO:0000269|PubMed:24012422,
CC ECO:0000269|PubMed:24095729}.
CC -!- PTM: Phosphorylation by RIPK3 induces a conformational switch that is
CC required for necroptosis (PubMed:24012422, PubMed:24095729,
CC PubMed:32200799). It also induces homotrimerization and localization to
CC the plasma membrane (By similarity). {ECO:0000250|UniProtKB:Q8NB16,
CC ECO:0000269|PubMed:24012422, ECO:0000269|PubMed:24095729,
CC ECO:0000269|PubMed:32200799}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype: mice are viable, fertile
CC and do not developmental or homeostatic phenotype in the absence of
CC overt stress (PubMed:23835476, PubMed:24012422). However, these mice
CC are resistant to TNF-induced necroptosis (PubMed:23835476,
CC PubMed:24012422). At a modestly lethal dose of influenza A virus (IAV),
CC mice do not display increased rates of mortality (PubMed:27321907,
CC PubMed:32200799). Perinatal lethality observed in Ripk1 knockout mice
CC is rescued in knockout mice lacking both Ripk1 and Mlkl
CC (PubMed:27819681). {ECO:0000269|PubMed:23835476,
CC ECO:0000269|PubMed:24012422, ECO:0000269|PubMed:27321907,
CC ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:32200799}.
CC -!- MISCELLANEOUS: In contrast to human protein, not inhibited by
CC necrosulfonamide, because a Trp residue is present instead of a Cys in
CC position 85. {ECO:0000305|PubMed:22265413}.
CC -!- MISCELLANEOUS: Interaction with RIPK3 is species specific: mouse MLKL
CC only interacts with mouse RIPK3 and not human RIPK3.
CC {ECO:0000305|PubMed:22265413}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. {ECO:0000305}.
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DR EMBL; AK018636; BAB31320.1; -; mRNA.
DR EMBL; AK170260; BAE41668.1; -; mRNA.
DR EMBL; BC023755; AAH23755.1; -; mRNA.
DR CCDS; CCDS52671.1; -. [Q9D2Y4-2]
DR CCDS; CCDS80932.1; -. [Q9D2Y4-1]
DR RefSeq; NP_001297542.1; NM_001310613.1. [Q9D2Y4-1]
DR RefSeq; NP_083281.1; NM_029005.3. [Q9D2Y4-2]
DR RefSeq; XP_006531505.1; XM_006531442.2. [Q9D2Y4-1]
DR PDB; 4BTF; X-ray; 2.60 A; A=1-472.
DR PDB; 4M68; X-ray; 1.70 A; A=182-472.
DR PDB; 4M69; X-ray; 2.50 A; B=182-472.
DR PDBsum; 4BTF; -.
DR PDBsum; 4M68; -.
DR PDBsum; 4M69; -.
DR AlphaFoldDB; Q9D2Y4; -.
DR SMR; Q9D2Y4; -.
DR BioGRID; 216850; 5.
DR IntAct; Q9D2Y4; 4.
DR STRING; 10090.ENSMUSP00000055521; -.
DR iPTMnet; Q9D2Y4; -.
DR PhosphoSitePlus; Q9D2Y4; -.
DR EPD; Q9D2Y4; -.
DR MaxQB; Q9D2Y4; -.
DR PaxDb; Q9D2Y4; -.
DR PeptideAtlas; Q9D2Y4; -.
DR PRIDE; Q9D2Y4; -.
DR ProteomicsDB; 290258; -. [Q9D2Y4-1]
DR ProteomicsDB; 290259; -. [Q9D2Y4-2]
DR Antibodypedia; 2097; 366 antibodies from 38 providers.
DR DNASU; 74568; -.
DR Ensembl; ENSMUST00000056157; ENSMUSP00000055521; ENSMUSG00000012519. [Q9D2Y4-1]
DR Ensembl; ENSMUST00000120432; ENSMUSP00000113718; ENSMUSG00000012519. [Q9D2Y4-2]
DR GeneID; 74568; -.
DR KEGG; mmu:74568; -.
DR UCSC; uc009nmd.1; mouse. [Q9D2Y4-2]
DR UCSC; uc009nme.1; mouse. [Q9D2Y4-1]
DR CTD; 197259; -.
DR MGI; MGI:1921818; Mlkl.
DR VEuPathDB; HostDB:ENSMUSG00000012519; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00390000016453; -.
DR HOGENOM; CLU_044216_0_0_1; -.
DR InParanoid; Q9D2Y4; -.
DR OMA; ESKVDWM; -.
DR OrthoDB; 1388260at2759; -.
DR PhylomeDB; Q9D2Y4; -.
DR TreeFam; TF328453; -.
DR Reactome; R-MMU-3295583; TRP channels.
DR Reactome; R-MMU-5213460; RIPK1-mediated regulated necrosis.
DR Reactome; R-MMU-5675482; Regulation of necroptotic cell death.
DR BioGRID-ORCS; 74568; 1 hit in 77 CRISPR screens.
DR ChiTaRS; Mlkl; mouse.
DR PRO; PR:Q9D2Y4; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q9D2Y4; protein.
DR Bgee; ENSMUSG00000012519; Expressed in bone marrow and 94 other tissues.
DR ExpressionAtlas; Q9D2Y4; baseline and differential.
DR Genevisible; Q9D2Y4; MM.
DR GO; GO:0030054; C:cell junction; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA: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; ISO:MGI.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:InterPro.
DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB.
DR GO; GO:0097528; P:execution phase of necroptosis; IDA: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; ISS: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..472
FT /note="Mixed lineage kinase domain-like protein"
FT /id="PRO_0000248240"
FT DOMAIN 192..456
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..143
FT /note="N-terminal bundle and brace (NBB); mediates INSP6
FT binding"
FT /evidence="ECO:0000250|UniProtKB:Q8NB16"
FT COILED 61..81
FT /evidence="ECO:0000255"
FT COILED 138..229
FT /evidence="ECO:0000255"
FT BINDING 198..206
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 219
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 124
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8NB16"
FT MOD_RES 345
FT /note="Phosphoserine; by RIPK3"
FT /evidence="ECO:0000269|PubMed:24012422,
FT ECO:0000269|PubMed:24095729"
FT MOD_RES 347
FT /note="Phosphoserine; by RIPK3"
FT /evidence="ECO:0000269|PubMed:24012422,
FT ECO:0000269|PubMed:24095729"
FT MOD_RES 349
FT /note="Phosphothreonine; by RIPK3"
FT /evidence="ECO:0000269|PubMed:24012422,
FT ECO:0000269|PubMed:24095729"
FT MOD_RES 352
FT /note="Phosphoserine; by RIPK3"
FT /evidence="ECO:0000269|PubMed:24095729"
FT VAR_SEQ 449..456
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_052132"
FT MUTAGEN 219
FT /note="K->M: Abolishes ATP-binding and induces necroptosis
FT in absence of exogeous stimuli and independently of RIPK3."
FT /evidence="ECO:0000269|PubMed:24012422"
FT MUTAGEN 239
FT /note="E->M: Retains ATP-binding ability."
FT /evidence="ECO:0000269|PubMed:24012422"
FT MUTAGEN 280
FT /note="L->P: Impaired ability to induce necroptosis."
FT /evidence="ECO:0000269|PubMed:24012422"
FT MUTAGEN 343
FT /note="Q->M: Retains ATP-binding ability and induces
FT necroptosis in absence of exogeous stimuli and
FT independently of RIPK3."
FT /evidence="ECO:0000269|PubMed:24012422"
FT MUTAGEN 345
FT /note="S->D: Mimics phosphorylation state and induces
FT necroptosis in absence of exogeous stimuli and
FT independently of RIPK3.e."
FT /evidence="ECO:0000269|PubMed:24012422"
FT MUTAGEN 385
FT /note="F->I: No effect."
FT /evidence="ECO:0000269|PubMed:24012422"
FT MUTAGEN 404..405
FT /note="SK->AA: Impairs interaction with RIPK3."
FT /evidence="ECO:0000269|PubMed:24095729"
FT MUTAGEN 404
FT /note="S->A: Impairs interaction with RIPK3."
FT /evidence="ECO:0000269|PubMed:24095729"
FT HELIX 3..18
FT /evidence="ECO:0007829|PDB:4BTF"
FT STRAND 22..24
FT /evidence="ECO:0007829|PDB:4BTF"
FT HELIX 25..47
FT /evidence="ECO:0007829|PDB:4BTF"
FT HELIX 55..77
FT /evidence="ECO:0007829|PDB:4BTF"
FT HELIX 98..114
FT /evidence="ECO:0007829|PDB:4BTF"
FT HELIX 132..154
FT /evidence="ECO:0007829|PDB:4BTF"
FT HELIX 159..168
FT /evidence="ECO:0007829|PDB:4BTF"
FT HELIX 188..190
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 196..200
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 202..211
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 214..223
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 229..242
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 254..260
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 263..265
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 267..273
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 280..286
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 292..311
FT /evidence="ECO:0007829|PDB:4M68"
FT TURN 321..323
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 324..327
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 328..330
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 331..334
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 336..339
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 340..347
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 359..362
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 366..370
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 378..394
FT /evidence="ECO:0007829|PDB:4M68"
FT TURN 398..401
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 404..412
FT /evidence="ECO:0007829|PDB:4M68"
FT STRAND 422..424
FT /evidence="ECO:0007829|PDB:4M69"
FT HELIX 426..435
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 440..442
FT /evidence="ECO:0007829|PDB:4M68"
FT HELIX 457..462
FT /evidence="ECO:0007829|PDB:4M68"
SQ SEQUENCE 472 AA; 54317 MW; 75E0E3E3DDB5DFB2 CRC64;
MDKLGQIIKL GQLIYEQCEK MKYCRKQCQR LGNRVHGLLQ PLQRLQAQGK KNLPDDITAA
LGRFDEVLKE ANQQIEKFSK KSHIWKFVSV GNDKILFHEV NEKLRDVWEE LLLLLQVYHW
NTVSDVSQPA SWQQEDRQDA EEDGNENMKV ILMQLQISVE EINKTLKQCS LKPTQEIPQD
LQIKEIPKEH LGPPWTKLKT SKMSTIYRGE YHRSPVTIKV FNNPQAESVG IVRFTFNDEI
KTMKKFDSPN ILRIFGICID QTVKPPEFSI VMEYCELGTL RELLDREKDL TMSVRSLLVL
RAARGLYRLH HSETLHRNIS SSSFLVAGGY QVKLAGFELS KTQNSISRTA KSTKAERSSS
TIYVSPERLK NPFCLYDIKA EIYSFGIVLW EIATGKIPFE GCDSKKIREL VAEDKKQEPV
GQDCPELLRE IINECRAHEP SQRPSVDGRS LSGRERILER LSAVEESTDK KV
