IPMK_HUMAN
ID IPMK_HUMAN Reviewed; 416 AA.
AC Q8NFU5;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Inositol polyphosphate multikinase;
DE EC=2.7.1.140 {ECO:0000269|PubMed:12223481};
DE EC=2.7.1.151 {ECO:0000269|PubMed:12027805, ECO:0000269|PubMed:12223481, ECO:0000269|PubMed:28882892, ECO:0000269|PubMed:30624931};
DE EC=2.7.1.153 {ECO:0000250|UniProtKB:Q99NI4};
DE AltName: Full=Inositol 1,3,4,6-tetrakisphosphate 5-kinase {ECO:0000303|PubMed:12223481};
GN Name=IPMK; Synonyms=IMPK {ECO:0000303|PubMed:29883610};
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], FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF
RP 322-ARG-LYS-323 AND 327-LYS-LYS-328, AND SUBCELLULAR LOCATION.
RX PubMed=12027805; DOI=10.1042/bj20020327;
RA Nalaskowski M.M., Deschermeier C., Fanick W., Mayr G.W.;
RT "The human homologue of yeast ArgRIII protein is an inositol phosphate
RT multikinase with predominantly nuclear localization.";
RL Biochem. J. 366:549-556(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE SPECIFICITY.
RX PubMed=12223481; DOI=10.1074/jbc.m206134200;
RA Chang S.-C., Miller A.L., Feng Y., Wente S.R., Majerus P.W.;
RT "The human homolog of the rat inositol phosphate multikinase is an inositol
RT 1,3,4,6-tetrakisphosphate 5-kinase.";
RL J. Biol. Chem. 277:43836-43843(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7, AND IDENTIFICATION BY MASS
RP 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 [5]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE
RP ANALYSIS] AT SER-7, CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE
RP ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [6]
RP IDENTIFICATION BY 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 [7]
RP FUNCTION.
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 [8] {ECO:0007744|PDB:5W2G, ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 50-262 AND 378-416 IN COMPLEXES
RP WITH ADP; MAGNESIUM AND MYOINOSITOL-TRISPHOSPHATE, FUNCTION, PATHWAY,
RP CATALYTIC ACTIVITY, AND MUTAGENESIS OF GLN-78; ARG-82; LYS-160; GLN-163;
RP GLN-164; LYS-167; GLN-196 AND HIS-388.
RX PubMed=28882892; DOI=10.1074/jbc.m117.801845;
RA Wang H., Shears S.B.;
RT "Structural features of human inositol phosphate multikinase rationalize
RT its inositol phosphate kinase and phosphoinositide 3-kinase activities.";
RL J. Biol. Chem. 292:18192-18202(2017).
RN [9] {ECO:0007744|PDB:6E7F}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 70-278 AND 374-416, CATALYTIC
RP ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF
RP 2-ALA--PRO-69 AND 279-SER--CYS-373.
RX PubMed=30420721; DOI=10.1038/s41598-018-34941-3;
RA Seacrist C.D., Blind R.D.;
RT "Crystallographic and kinetic analyses of human IPMK reveal disordered
RT domains modulate ATP binding and kinase activity.";
RL Sci. Rep. 8:16672-16672(2018).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 50-279 AND 378-416 IN COMPLEXES
RP WITH FLAVONOIDS, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND ACTIVITY
RP REGULATION.
RX PubMed=30624931; DOI=10.1021/acs.jmedchem.8b01593;
RA Gu C., Stashko M.A., Puhl-Rubio A.C., Chakraborty M., Chakraborty A.,
RA Frye S.V., Pearce K.H., Wang X., Shears S.B., Wang H.;
RT "Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related
RT Flavonoids: A Structure-Activity Analysis.";
RL J. Med. Chem. 62:1443-1454(2019).
CC -!- FUNCTION: Inositol phosphate kinase with a broad substrate specificity
CC (PubMed:12027805, PubMed:12223481, PubMed:28882892, PubMed:30420721,
CC PubMed:30624931). Phosphorylates inositol 1,4,5-trisphosphate
CC (Ins(1,4,5)P3) first to inositol 1,3,4,5-tetrakisphosphate and then to
CC inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5)
CC (PubMed:12027805, PubMed:12223481, PubMed:28882892, PubMed:30624931).
CC Phosphorylates inositol 1,3,4,6-tetrakisphosphate (Ins(1,3,4,6)P4)
CC (PubMed:12223481). Phosphorylates glycero-3-phospho-1D-myo-inositol
CC 4,5-bisphosphate to glycero-3-phospho-1D-myo-inositol 3,4,5-
CC trisphosphate (PubMed:30420721, PubMed:28882892). Plays an important
CC role in MLKL-mediated necroptosis via its role in the biosynthesis of
CC inositol pentakisphosphate (InsP5) and inositol hexakisphosphate
CC (InsP6). Binding of these highly phosphorylated inositol phosphates to
CC MLKL mediates the release of an N-terminal auto-inhibitory region,
CC leading to activation of the kinase. Essential for activated phospho-
CC MLKL to oligomerize and localize to the cell membrane during
CC necroptosis (PubMed:29883610). Required for normal embryonic
CC development, probably via its role in the biosynthesis of inositol
CC 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) and inositol
CC hexakisphosphate (InsP6) (By similarity).
CC {ECO:0000250|UniProtKB:Q7TT16, ECO:0000269|PubMed:12027805,
CC ECO:0000269|PubMed:12223481, ECO:0000269|PubMed:28882892,
CC ECO:0000269|PubMed:29883610, ECO:0000269|PubMed:30420721,
CC ECO:0000269|PubMed:30624931}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1D-myo-inositol 1,4,5-trisphosphate + 2 ATP = 1D-myo-inositol
CC 1,3,4,5,6-pentakisphosphate + 2 ADP + 2 H(+); Xref=Rhea:RHEA:32359,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57733,
CC ChEBI:CHEBI:203600, ChEBI:CHEBI:456216; EC=2.7.1.151;
CC Evidence={ECO:0000269|PubMed:12027805, ECO:0000269|PubMed:12223481,
CC ECO:0000269|PubMed:28882892, ECO:0000269|PubMed:30624931};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1D-myo-inositol 1,3,4,6-tetrakisphosphate + ATP = 1D-myo-
CC inositol 1,3,4,5,6-pentakisphosphate + ADP + H(+);
CC Xref=Rhea:RHEA:12717, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:57660, ChEBI:CHEBI:57733, ChEBI:CHEBI:456216;
CC EC=2.7.1.140; Evidence={ECO:0000269|PubMed:12223481};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-octadecanoyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-
CC 3-phospho-1D-myo-inositol 4,5-bisphosphate + ATP = 1-octadecanoyl-2-
CC (5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phospho-(1D-myo-
CC inositol 3,4,5-triphosphate) + ADP + H(+); Xref=Rhea:RHEA:43396,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:77137,
CC ChEBI:CHEBI:83243, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000305|PubMed:28882892, ECO:0000305|PubMed:30420721};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-
CC bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3,4,5-trisphosphate) + ADP + H(+); Xref=Rhea:RHEA:21292,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57836,
CC ChEBI:CHEBI:58456, ChEBI:CHEBI:456216; EC=2.7.1.153;
CC Evidence={ECO:0000250|UniProtKB:Q99NI4};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21293;
CC Evidence={ECO:0000250|UniProtKB:Q99NI4};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000305|PubMed:28882892, ECO:0000305|PubMed:30624931};
CC Note=Binds two Mg(2+), but the interaction with the protein is mostly
CC indirect. {ECO:0000269|PubMed:30624931};
CC -!- ACTIVITY REGULATION: Inhibited by flavonoids that occupy the ATP-
CC binding pocket. Inhibited by myricetin, quercetin, luteolin,
CC kaempferol, isorhamnetin and diosmetin, and to a lesser degree by
CC rhamnetin and apigenin. {ECO:0000269|PubMed:30624931}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=112 nM for myo-inositol-1,4,5-trisphosphate
CC {ECO:0000269|PubMed:12223481};
CC KM=295 nM for myo-inositol-1,3,4,6-tetrakisphosphate
CC {ECO:0000269|PubMed:12223481};
CC KM=129 nM for myo-inositol-1,3,4,5-tetrakisphosphate
CC {ECO:0000269|PubMed:12223481};
CC KM=61 uM for ATP {ECO:0000269|PubMed:30420721};
CC KM=39 uM for phosphatidylinositol 4,5-bisphosphate
CC {ECO:0000269|PubMed:30420721};
CC Vmax=27 nmol/min/mg enzyme with myo-inositol-1,4,5-trisphosphate as
CC substrate {ECO:0000269|PubMed:12223481};
CC Vmax=114 nmol/min/mg enzyme with myo-inositol-1,3,4,6-
CC tetrakisphosphate as substrate {ECO:0000269|PubMed:12223481};
CC Vmax=1.1 nmol/min/mg enzyme with myo-inositol-1,3,4,5-
CC tetrakisphosphate as substrate {ECO:0000269|PubMed:12223481};
CC -!- PATHWAY: Phospholipid metabolism; phosphatidylinositol metabolism.
CC {ECO:0000269|PubMed:12027805, ECO:0000269|PubMed:12223481,
CC ECO:0000269|PubMed:28882892, ECO:0000269|PubMed:30624931}.
CC -!- INTERACTION:
CC Q8NFU5; O75031: HSF2BP; NbExp=3; IntAct=EBI-11347579, EBI-7116203;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12027805}.
CC -!- TISSUE SPECIFICITY: Ubiquitous, with the highest expression in skeletal
CC muscle, liver, placenta, lung, peripheral blood leukocytes, kidney,
CC spleen and colon. {ECO:0000269|PubMed:12223481}.
CC -!- SIMILARITY: Belongs to the inositol phosphokinase (IPK) family.
CC {ECO:0000305}.
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DR EMBL; AF432853; AAM97838.1; -; mRNA.
DR EMBL; BK000580; DAA01362.1; -; mRNA.
DR EMBL; BC065709; AAH65709.1; -; mRNA.
DR CCDS; CCDS7250.1; -.
DR RefSeq; NP_689416.1; NM_152230.4.
DR PDB; 5W2G; X-ray; 1.80 A; A=50-262, A=378-416.
DR PDB; 5W2H; X-ray; 1.90 A; A=50-262, A=378-416.
DR PDB; 5W2I; X-ray; 1.60 A; A=50-262, A=378-416.
DR PDB; 6E7F; X-ray; 2.50 A; A/B=70-279, A/B=374-416.
DR PDB; 6M88; X-ray; 1.90 A; A=50-262, A=378-416.
DR PDB; 6M89; X-ray; 1.85 A; A=50-262, A=378-416.
DR PDB; 6M8A; X-ray; 1.75 A; A=50-262, A=378-416.
DR PDB; 6M8B; X-ray; 1.80 A; A=50-262, A=378-416.
DR PDB; 6M8C; X-ray; 1.80 A; A=50-262, A=378-416.
DR PDB; 6M8D; X-ray; 2.00 A; A=50-262, A=378-416.
DR PDB; 6M8E; X-ray; 2.00 A; A=50-262, A=378-416.
DR PDBsum; 5W2G; -.
DR PDBsum; 5W2H; -.
DR PDBsum; 5W2I; -.
DR PDBsum; 6E7F; -.
DR PDBsum; 6M88; -.
DR PDBsum; 6M89; -.
DR PDBsum; 6M8A; -.
DR PDBsum; 6M8B; -.
DR PDBsum; 6M8C; -.
DR PDBsum; 6M8D; -.
DR PDBsum; 6M8E; -.
DR AlphaFoldDB; Q8NFU5; -.
DR SMR; Q8NFU5; -.
DR BioGRID; 128968; 7.
DR IntAct; Q8NFU5; 4.
DR STRING; 9606.ENSP00000363046; -.
DR BindingDB; Q8NFU5; -.
DR ChEMBL; CHEMBL4523401; -.
DR iPTMnet; Q8NFU5; -.
DR PhosphoSitePlus; Q8NFU5; -.
DR BioMuta; IPMK; -.
DR DMDM; 50401072; -.
DR EPD; Q8NFU5; -.
DR jPOST; Q8NFU5; -.
DR MassIVE; Q8NFU5; -.
DR MaxQB; Q8NFU5; -.
DR PaxDb; Q8NFU5; -.
DR PeptideAtlas; Q8NFU5; -.
DR PRIDE; Q8NFU5; -.
DR ProteomicsDB; 73362; -.
DR Antibodypedia; 28039; 195 antibodies from 27 providers.
DR DNASU; 253430; -.
DR Ensembl; ENST00000373935.4; ENSP00000363046.3; ENSG00000151151.6.
DR GeneID; 253430; -.
DR KEGG; hsa:253430; -.
DR MANE-Select; ENST00000373935.4; ENSP00000363046.3; NM_152230.5; NP_689416.1.
DR UCSC; uc001jkb.3; human.
DR CTD; 253430; -.
DR DisGeNET; 253430; -.
DR GeneCards; IPMK; -.
DR HGNC; HGNC:20739; IPMK.
DR HPA; ENSG00000151151; Low tissue specificity.
DR MalaCards; IPMK; -.
DR MIM; 609851; gene.
DR neXtProt; NX_Q8NFU5; -.
DR OpenTargets; ENSG00000151151; -.
DR Orphanet; 456333; Hereditary neuroendocrine tumor of small intestine.
DR PharmGKB; PA134903369; -.
DR VEuPathDB; HostDB:ENSG00000151151; -.
DR eggNOG; KOG1620; Eukaryota.
DR GeneTree; ENSGT00940000155309; -.
DR HOGENOM; CLU_042569_0_0_1; -.
DR InParanoid; Q8NFU5; -.
DR OMA; YGFCITG; -.
DR OrthoDB; 902814at2759; -.
DR PhylomeDB; Q8NFU5; -.
DR TreeFam; TF321442; -.
DR BioCyc; MetaCyc:HS07712-MON; -.
DR BRENDA; 2.7.1.151; 2681.
DR PathwayCommons; Q8NFU5; -.
DR Reactome; R-HSA-1855191; Synthesis of IPs in the nucleus.
DR SABIO-RK; Q8NFU5; -.
DR SignaLink; Q8NFU5; -.
DR UniPathway; UPA00949; -.
DR BioGRID-ORCS; 253430; 38 hits in 1069 CRISPR screens.
DR ChiTaRS; IPMK; human.
DR GenomeRNAi; 253430; -.
DR Pharos; Q8NFU5; Tbio.
DR PRO; PR:Q8NFU5; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q8NFU5; protein.
DR Bgee; ENSG00000151151; Expressed in buccal mucosa cell and 187 other tissues.
DR Genevisible; Q8NFU5; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0097243; F:flavonoid binding; IDA:UniProtKB.
DR GO; GO:0000824; F:inositol tetrakisphosphate 3-kinase activity; TAS:Reactome.
DR GO; GO:0047326; F:inositol tetrakisphosphate 5-kinase activity; TAS:Reactome.
DR GO; GO:0000825; F:inositol tetrakisphosphate 6-kinase activity; IMP:UniProtKB.
DR GO; GO:0051765; F:inositol tetrakisphosphate kinase activity; IBA:GO_Central.
DR GO; GO:0008440; F:inositol-1,4,5-trisphosphate 3-kinase activity; IDA:UniProtKB.
DR GO; GO:0000823; F:inositol-1,4,5-trisphosphate 6-kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0016301; F:kinase activity; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0102732; F:myo-inositol-1,2,3,4,6-heptakisphosphate 5-kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0052812; F:phosphatidylinositol-3,4-bisphosphate 5-kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; ISS:UniProtKB.
DR GO; GO:0032958; P:inositol phosphate biosynthetic process; IBA:GO_Central.
DR GO; GO:0043647; P:inositol phosphate metabolic process; TAS:Reactome.
DR GO; GO:0032957; P:inositol trisphosphate metabolic process; IDA:UniProtKB.
DR GO; GO:0070266; P:necroptotic process; IMP:UniProtKB.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR Gene3D; 3.30.470.160; -; 1.
DR InterPro; IPR005522; IPK.
DR InterPro; IPR038286; IPK_sf.
DR PANTHER; PTHR12400; PTHR12400; 1.
DR Pfam; PF03770; IPK; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Kinase; Lipid metabolism;
KW Magnesium; Metal-binding; Nucleotide-binding; Nucleus;
KW Phospholipid metabolism; Phosphoprotein; Reference proteome; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19369195"
FT CHAIN 2..416
FT /note="Inositol polyphosphate multikinase"
FT /id="PRO_0000066870"
FT REGION 1..38
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 320..330
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000305|PubMed:12027805"
FT BINDING 75
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I"
FT BINDING 82
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I"
FT BINDING 131..133
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I"
FT BINDING 144
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I"
FT BINDING 146
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I"
FT BINDING 160..167
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H"
FT BINDING 196
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I"
FT BINDING 385
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I"
FT BINDING 388
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:28882892,
FT ECO:0007744|PDB:5W2H, ECO:0007744|PDB:5W2I"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 7
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19369195"
FT VARIANT 349
FT /note="M -> I (in dbSNP:rs2275443)"
FT /id="VAR_022112"
FT MUTAGEN 2..69
FT /note="Missing: No effect on affinity for
FT phosphatidylinositol 4,5-bisphosphate and mildly increased
FT enzyme activity; when associated with 279-S--V-365 DEL and
FT 366-G--S-373."
FT /evidence="ECO:0000269|PubMed:30420721"
FT MUTAGEN 78
FT /note="Q->A: Strongly decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 82
FT /note="R->A: Strongly decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 144
FT /note="D->N: Loss of kinase activity and ability to execute
FT necroptosis; when associated with A-146."
FT /evidence="ECO:0000269|PubMed:29883610"
FT MUTAGEN 146
FT /note="K->A: Loss of kinase activity and ability to execute
FT necroptosis; when associated with N-144."
FT /evidence="ECO:0000269|PubMed:29883610"
FT MUTAGEN 160
FT /note="K->A: Strongly decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 163
FT /note="Q->A: Moderately decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 163
FT /note="Q->R: Decreased activity with inositol 1,4,5-
FT trisphosphate. No effect on phosphorylation of inositol
FT 1,3,4,5-tetrakisphosphate."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 164
FT /note="Q->A: Strongly decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 164
FT /note="Q->R: Decreased activity with inositol 1,4,5-
FT trisphosphate. Increased phosphorylation of inositol
FT 1,3,4,5-tetrakisphosphate."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 167
FT /note="K->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 196
FT /note="Q->A: Decreased enzyme activity."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 196
FT /note="Q->R: Decreased activity with inositol 1,4,5-
FT trisphosphate. Increased phosphorylation of inositol
FT 1,3,4,5-tetrakisphosphate."
FT /evidence="ECO:0000269|PubMed:28882892"
FT MUTAGEN 279..365
FT /note="Missing: No effect on affinity for
FT phosphatidylinositol 4,5-bisphosphate and mildly increased
FT enzyme activity; when associated with 2-A--P-69 DEL and
FT 366-G--S-373 DEL."
FT /evidence="ECO:0000269|PubMed:30420721"
FT MUTAGEN 322..323
FT /note="RK->QQ: Interferes with nuclear localization."
FT /evidence="ECO:0000269|PubMed:12027805"
FT MUTAGEN 327..328
FT /note="KK->QQ: Interferes with nuclear localization."
FT /evidence="ECO:0000269|PubMed:12027805"
FT MUTAGEN 366..373
FT /note="FYHLPTGC->GGGGSGGGGS: No effect on affinity for
FT phosphatidylinositol 4,5-bisphosphate and mildly increased
FT enzyme activity; when associated with 2-A--P-69 DEL and
FT 279-S--V-365 DEL."
FT /evidence="ECO:0000269|PubMed:30420721"
FT MUTAGEN 388
FT /note="H->A: Loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:28882892"
FT STRAND 66..68
FT /evidence="ECO:0007829|PDB:5W2I"
FT TURN 69..71
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 72..76
FT /evidence="ECO:0007829|PDB:5W2I"
FT TURN 79..81
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 82..93
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 101..106
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 107..109
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 113..117
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 127..131
FT /evidence="ECO:0007829|PDB:5W2I"
FT TURN 133..136
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 138..149
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 158..167
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 171..174
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 175..185
FT /evidence="ECO:0007829|PDB:5W2I"
FT TURN 186..189
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 190..194
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 196..200
FT /evidence="ECO:0007829|PDB:5W2I"
FT TURN 204..206
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 207..212
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 213..215
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 218..221
FT /evidence="ECO:0007829|PDB:6M8A"
FT HELIX 223..241
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 245..258
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 379..384
FT /evidence="ECO:0007829|PDB:5W2I"
FT STRAND 389..391
FT /evidence="ECO:0007829|PDB:5W2I"
FT HELIX 397..413
FT /evidence="ECO:0007829|PDB:5W2I"
SQ SEQUENCE 416 AA; 47222 MW; 622D678696A892F9 CRC64;
MATEPPSPLR VEAPGPPEMR TSPAIESTPE GTPQPAGGRL RFLNGCVPLS HQVAGHMYGK
DKVGILQHPD GTVLKQLQPP PRGPRELEFY NMVYAADCFD GVLLELRKYL PKYYGIWSPP
TAPNDLYLKL EDVTHKFNKP CIMDVKIGQK SYDPFASSEK IQQQVSKYPL MEEIGFLVLG
MRVYHVHSDS YETENQHYGR SLTKETIKDG VSRFFHNGYC LRKDAVAASI QKIEKILQWF
ENQKQLNFYA SSLLFVYEGS SQPTTTKLND RTLAEKFLSK GQLSDTEVLE YNNNFHVLSS
TANGKIESSV GKSLSKMYAR HRKIYTKKHH SQTSLKVENL EQDNGWKSMS QEHLNGNVLS
QLEKVFYHLP TGCQEIAEVE VRMIDFAHVF PSNTIDEGYV YGLKHLISVL RSILDN
