KSR1_MOUSE
ID KSR1_MOUSE Reviewed; 873 AA.
AC Q61097; Q61648; Q78DX8;
DT 21-DEC-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 186.
DE RecName: Full=Kinase suppressor of Ras 1;
DE Short=mKSR1;
DE EC=2.7.11.1 {ECO:0000269|PubMed:21441104};
DE AltName: Full=Protein Hb;
GN Name=Ksr1; Synonyms=Ksr;
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]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8521512; DOI=10.1016/0092-8674(95)90204-x;
RA Therrien M., Chang H.C., Solomon N.M., Karim F.D., Wassarman D.A.,
RA Rubin G.M.;
RT "KSR, a novel protein kinase required for RAS signal transduction.";
RL Cell 83:879-888(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2), INTERACTION WITH MAPK, MUTAGENESIS
RP OF GLY-572; ARG-589; ARG-615; ASP-700 AND CYS-809, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=10891492; DOI=10.1128/mcb.20.15.5529-5539.2000;
RA Mueller J., Cacace A.M., Lyons W.E., McGill C.B., Morrison D.K.;
RT "Identification of B-KSR1, a novel brain-specific isoform of KSR1 that
RT functions in neuronal signaling.";
RL Mol. Cell. Biol. 20:5529-5539(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Pelan S.;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 49-474 (ISOFORMS 1/2).
RC STRAIN=BALB/cJ;
RX PubMed=7626882; DOI=10.1007/bf00364794;
RA Nehls M., Luno K., Schorpp M., Pfeifer D., Krause S., Matysiak-Scholze U.,
RA Dierbach H., Boehm T.;
RT "YAC/P1 contigs defining the location of 56 microsatellite markers and
RT several genes across a 3.4cM interval on mouse chromosome 11.";
RL Mamm. Genome 6:321-331(1995).
RN [5]
RP FUNCTION, INTERACTION WITH MAP2K1; MAP2K2; HSP90AA1; YWHAB AND CDC37,
RP SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF 56-LEU--ARG-57; GLY-580;
RP ARG-589; ARG-615 AND CYS-809.
RX PubMed=10409742; DOI=10.1128/mcb.19.8.5523;
RA Stewart S., Sundaram M., Zhang Y., Lee J., Han M., Guan K.L.;
RT "Kinase suppressor of Ras forms a multiprotein signaling complex and
RT modulates MEK localization.";
RL Mol. Cell. Biol. 19:5523-5534(1999).
RN [6]
RP INTERACTION WITH MARK3 AND 14-3-3, PHOSPHORYLATION AT SER-297 AND SER-392,
RP MUTAGENESIS OF SER-297; SER-392; ILE-397 AND VAL-401, AND SUBCELLULAR
RP LOCATION.
RX PubMed=11741534; DOI=10.1016/s1097-2765(01)00383-5;
RA Mueller J., Ory S., Copeland T., Piwnica-Worms H., Morrison D.K.;
RT "C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold,
RT KSR1.";
RL Mol. Cell 8:983-993(2001).
RN [7]
RP FUNCTION, INTERACTION WITH PPP2R1A AND PPP2CA, DEPHOSPHORYLATION BY PPP2CA,
RP AND SUBCELLULAR LOCATION.
RX PubMed=12932319; DOI=10.1016/s0960-9822(03)00535-9;
RA Ory S., Zhou M., Conrads T.P., Veenstra T.D., Morrison D.K.;
RT "Protein phosphatase 2A positively regulates Ras signaling by
RT dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites.";
RL Curr. Biol. 13:1356-1364(2003).
RN [8]
RP REVIEW.
RX PubMed=12007434; DOI=10.1016/s0960-9822(02)00831-x;
RA Roy F., Therrien M.;
RT "MAP kinase module: the Ksr connection.";
RL Curr. Biol. 12:R325-R327(2002).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-320; SER-392 AND SER-518, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Kidney, Lung, 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 [10]
RP FUNCTION, INTERACTION WITH AKAP13; MAP2K1 AND BRAF, IDENTIFICATION BY MASS
RP SPECTROMETRY, PHOSPHORYLATION AT SER-838, AND MUTAGENESIS OF SER-838.
RX PubMed=21102438; DOI=10.1038/ncb2130;
RA Smith F.D., Langeberg L.K., Cellurale C., Pawson T., Morrison D.K.,
RA Davis R.J., Scott J.D.;
RT "AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade.";
RL Nat. Cell Biol. 12:1242-1249(2010).
RN [11]
RP STRUCTURE BY NMR OF 331-378 IN COMPLEX WITH ZINC.
RX PubMed=11786023; DOI=10.1006/jmbi.2001.5263;
RA Zhou M., Horita D.A., Waugh D.S., Byrd R.A., Morrison D.K.;
RT "Solution structure and functional analysis of the cysteine-rich C1 domain
RT of kinase suppressor of Ras (KSR).";
RL J. Mol. Biol. 315:435-446(2002).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH BRAF AND MAP2K1, AND
RP MUTAGENESIS OF ALA-587.
RX PubMed=21441104; DOI=10.1073/pnas.1102554108;
RA Hu J., Yu H., Kornev A.P., Zhao J., Filbert E.L., Taylor S.S., Shaw A.S.;
RT "Mutation that blocks ATP binding creates a pseudokinase stabilizing the
RT scaffolding function of kinase suppressor of Ras, CRAF and BRAF.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:6067-6072(2011).
RN [13] {ECO:0007744|PDB:2LPE}
RP STRUCTURE BY NMR OF 25-170, INTERACTION WITH BRAF AND MAP2K1, DOMAIN,
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 56-LEU-ARG-57; ILE-71 AND LEU-78.
RX PubMed=23250398; DOI=10.1126/scisignal.2003289;
RA Koveal D., Schuh-Nuhfer N., Ritt D., Page R., Morrison D.K., Peti W.;
RT "A CC-SAM, for coiled coil-sterile alpha motif, domain targets the scaffold
RT KSR-1 to specific sites in the plasma membrane.";
RL Sci. Signal. 5:RA94-RA94(2012).
CC -!- FUNCTION: Part of a multiprotein signaling complex which promotes
CC phosphorylation of Raf family members and activation of downstream MAP
CC kinases (PubMed:10409742, PubMed:12932319, PubMed:21102438,
CC PubMed:21441104). Independently of its kinase activity, acts as
CC MAP2K1/MEK1 and MAP2K2/MEK2-dependent allosteric activator of BRAF;
CC upon binding to MAP2K1/MEK1 or MAP2K2/MEK2, dimerizes with BRAF and
CC promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 and/or
CC MAP2K2/MEK2 (By similarity). Promotes activation of MAPK1 and/or MAPK3,
CC both in response to EGF and to cAMP (PubMed:21102438). Its kinase
CC activity is unsure (PubMed:21441104). Some protein kinase activity has
CC been detected in vitro, however the physiological relevance of this
CC activity is unknown (PubMed:21441104). {ECO:0000250|UniProtKB:Q8IVT5,
CC ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:12932319,
CC ECO:0000269|PubMed:21102438, ECO:0000269|PubMed:21441104}.
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:21441104};
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:21441104};
CC -!- SUBUNIT: Homodimer (By similarity). Heterodimerizes (via N-terminus)
CC with BRAF (via N-terminus) in a MAP2K1/MEK1 or MAP2K2/MEK2-dependent
CC manner (By similarity). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2
CC (PubMed:10891492, PubMed:10409742, PubMed:21441104). Binding to
CC MAP2K1/MEK1 releases the intramolecular inhibitory interaction between
CC KSR1 N-terminus and kinase domains which is required for the subsequent
CC RSK1 dimerization with BRAF (By similarity). Identified in a complex
CC with AKAP13, MAP2K1 and BRAF (PubMed:21102438, PubMed:23250398).
CC Interacts with AKAP13 and BRAF (PubMed:21102438). Interacts with RAF
CC and MAPK/ERK, in a Ras-dependent manner (PubMed:10891492). Interacts
CC with 14-3-3 proteins including YWHAB (PubMed:10409742,
CC PubMed:11741534). Interacts with HSP90AA1/HSP90, YWHAE/14-3-3 and CDC37
CC (PubMed:10409742). The binding of 14-3-3 proteins to phosphorylated
CC KSR1 prevents the membrane localization (PubMed:10409742). Interacts
CC with MARK3 (PubMed:11741534). Interacts with PPP2R1A and PPP2CA
CC (PubMed:12932319). Interacts with VRK2 (By similarity).
CC {ECO:0000250|UniProtKB:Q8IVT5, ECO:0000269|PubMed:10409742,
CC ECO:0000269|PubMed:10891492, ECO:0000269|PubMed:11741534,
CC ECO:0000269|PubMed:12932319, ECO:0000269|PubMed:21102438,
CC ECO:0000269|PubMed:21441104, ECO:0000269|PubMed:23250398}.
CC -!- INTERACTION:
CC Q61097; Q60875: Arhgef2; NbExp=5; IntAct=EBI-1536336, EBI-772191;
CC Q61097; P15056: BRAF; Xeno; NbExp=3; IntAct=EBI-1536336, EBI-365980;
CC Q61097; P15531: NME1; Xeno; NbExp=7; IntAct=EBI-1536336, EBI-741141;
CC Q61097; Q86Y07-1: VRK2; Xeno; NbExp=8; IntAct=EBI-1536336, EBI-1207633;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10409742,
CC ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319,
CC ECO:0000269|PubMed:23250398}. Membrane {ECO:0000269|PubMed:10409742};
CC Peripheral membrane protein {ECO:0000269|PubMed:10409742}. Cell
CC membrane {ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319,
CC ECO:0000269|PubMed:23250398}; Peripheral membrane protein
CC {ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319,
CC ECO:0000269|PubMed:23250398}. Cell projection, ruffle membrane
CC {ECO:0000269|PubMed:23250398}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q8IVT5}. Note=In unstimulated cells, where the
CC phosphorylated form is bound to a 14-3-3 protein, sequestration in the
CC cytoplasm occurs. Following growth factor treatment, the protein is
CC free for membrane translocation, and it moves from the cytoplasm to the
CC cell periphery. {ECO:0000305|PubMed:12932319}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q61097-1; Sequence=Displayed;
CC Name=2; Synonyms=B-KSR1;
CC IsoId=Q61097-2; Sequence=VSP_012232, VSP_012233;
CC -!- TISSUE SPECIFICITY: Expressed in brain, spleen and testis. Isoform 1 is
CC highly expressed spleen and weakly in testis, and isoform 2 is highly
CC expressed in brain and weakly in testis. {ECO:0000269|PubMed:10891492}.
CC -!- DOMAIN: The protein kinase domain is predicted to be catalytically
CC inactive. The domain is sufficient for KSR1 and KSR1-mediated MAP2K1
CC and MAP2K2 membrane localization. The domain is required but not
CC sufficient for MAP kinase-mediated inhibition of ELK1 phosphorylation
CC (PubMed:10409742). {ECO:0000255, ECO:0000269|PubMed:10409742}.
CC -!- DOMAIN: The N-terminal region mediates interaction with BRAF
CC (PubMed:23250398). Also mediates membrane localization
CC (PubMed:23250398). {ECO:0000269|PubMed:23250398}.
CC -!- PTM: Phosphorylated on Ser-297 and, to a higher extent, on Ser-392 by
CC MARK3 (PubMed:11741534). Dephosphorylated on Ser-392 by PPP2CA
CC (PubMed:12932319). Phosphorylated KSR1 is cytoplasmic and
CC dephosphorylated KSR1 is membrane-associated (Probable). Phosphorylated
CC by PKA at Ser-838. Phosphorylation at Ser-838 is required for cAMP-
CC dependent activation of MAPK1 and/or MAPK3 (PubMed:21102438).
CC {ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:10891492,
CC ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319,
CC ECO:0000269|PubMed:21102438, ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr
CC protein kinase family. {ECO:0000305}.
CC -!- CAUTION: Although it belongs to the protein kinase superfamily, the
CC ATP-binding motif VAIK has an arginine instead of a lysine residue
CC suggesting that KSR1 cannot bind ATP and therefore lacks protein kinase
CC activity. However, KSR1 is capable of binding ATP (PubMed:21441104).
CC Has protein kinase activity towards MAP2K1 in presence of RAF1/c-RAF in
CC vitro (PubMed:21441104). {ECO:0000269|PubMed:21441104, ECO:0000305}.
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DR EMBL; U43585; AAC52382.1; -; mRNA.
DR EMBL; AL592551; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; X81634; CAA57288.1; -; mRNA.
DR CCDS; CCDS25117.1; -. [Q61097-1]
DR PIR; I48379; I48379.
DR RefSeq; NP_001335136.1; NM_001348207.1.
DR RefSeq; NP_038599.1; NM_013571.3. [Q61097-1]
DR RefSeq; XP_006532398.1; XM_006532335.3. [Q61097-2]
DR PDB; 1KBE; NMR; -; A=331-378.
DR PDB; 1KBF; NMR; -; A=331-378.
DR PDB; 2LPE; NMR; -; A=25-170.
DR PDBsum; 1KBE; -.
DR PDBsum; 1KBF; -.
DR PDBsum; 2LPE; -.
DR AlphaFoldDB; Q61097; -.
DR BMRB; Q61097; -.
DR SMR; Q61097; -.
DR BioGRID; 201048; 239.
DR CORUM; Q61097; -.
DR IntAct; Q61097; 9.
DR MINT; Q61097; -.
DR STRING; 10090.ENSMUSP00000018478; -.
DR iPTMnet; Q61097; -.
DR PhosphoSitePlus; Q61097; -.
DR EPD; Q61097; -.
DR jPOST; Q61097; -.
DR MaxQB; Q61097; -.
DR PaxDb; Q61097; -.
DR PeptideAtlas; Q61097; -.
DR PRIDE; Q61097; -.
DR ProteomicsDB; 263568; -. [Q61097-1]
DR ProteomicsDB; 263569; -. [Q61097-2]
DR Antibodypedia; 2110; 438 antibodies from 33 providers.
DR DNASU; 16706; -.
DR Ensembl; ENSMUST00000018478; ENSMUSP00000018478; ENSMUSG00000018334. [Q61097-1]
DR GeneID; 16706; -.
DR KEGG; mmu:16706; -.
DR UCSC; uc033fyo.1; mouse. [Q61097-1]
DR CTD; 8844; -.
DR MGI; MGI:105051; Ksr1.
DR VEuPathDB; HostDB:ENSMUSG00000018334; -.
DR eggNOG; KOG0193; Eukaryota.
DR GeneTree; ENSGT00940000156066; -.
DR HOGENOM; CLU_006812_0_0_1; -.
DR InParanoid; Q61097; -.
DR OMA; HAIPHKW; -.
DR OrthoDB; 281487at2759; -.
DR PhylomeDB; Q61097; -.
DR TreeFam; TF317006; -.
DR Reactome; R-MMU-5673000; RAF activation.
DR Reactome; R-MMU-5674135; MAP2K and MAPK activation.
DR Reactome; R-MMU-5675221; Negative regulation of MAPK pathway.
DR BioGRID-ORCS; 16706; 2 hits in 74 CRISPR screens.
DR ChiTaRS; Ksr1; mouse.
DR EvolutionaryTrace; Q61097; -.
DR PRO; PR:Q61097; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q61097; protein.
DR Bgee; ENSMUSG00000018334; Expressed in hindlimb stylopod muscle and 180 other tissues.
DR ExpressionAtlas; Q61097; baseline and differential.
DR Genevisible; Q61097; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0016020; C:membrane; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0071889; F:14-3-3 protein binding; IPI:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IMP:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; IPI:UniProtKB.
DR GO; GO:0051879; F:Hsp90 protein binding; IPI:UniProtKB.
DR GO; GO:0005078; F:MAP-kinase scaffold activity; IDA:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031434; F:mitogen-activated protein kinase kinase binding; IPI:UniProtKB.
DR GO; GO:0008022; F:protein C-terminus binding; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; IMP:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0019933; P:cAMP-mediated signaling; IMP:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0007265; P:Ras protein signal transduction; IMP:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0043405; P:regulation of MAP kinase activity; IMP:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00029; C1; 1.
DR Gene3D; 1.10.150.50; -; 1.
DR InterPro; IPR046349; C1-like_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR025561; KSR_SAM-like_dom.
DR InterPro; IPR002219; PE/DAG-bd.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF13543; SAM_KSR1; 1.
DR SMART; SM00109; C1; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57889; SSF57889; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS00479; ZF_DAG_PE_1; 1.
DR PROSITE; PS50081; ZF_DAG_PE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane;
KW Cell projection; Cytoplasm; Endoplasmic reticulum; Kinase; Membrane;
KW Metal-binding; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Zinc; Zinc-finger.
FT CHAIN 1..873
FT /note="Kinase suppressor of Ras 1"
FT /id="PRO_0000086230"
FT DOMAIN 563..833
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT ZN_FING 333..377
FT /note="Phorbol-ester/DAG-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226"
FT REGION 1..170
FT /note="Mediates association with membranes"
FT /evidence="ECO:0000269|PubMed:23250398"
FT REGION 1..24
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 174..230
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 251..281
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 416..473
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 506..544
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 202..220
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 424..473
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 514..529
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 683
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 334
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:11786023"
FT BINDING 346
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:11786023"
FT BINDING 349
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:11786023"
FT BINDING 359
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:11786023"
FT BINDING 362
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:11786023"
FT BINDING 367
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:11786023"
FT BINDING 370
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:11786023"
FT BINDING 377
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:11786023"
FT BINDING 569..577
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 685
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q6VAB6"
FT BINDING 700
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q6VAB6"
FT MOD_RES 256
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8IVT5"
FT MOD_RES 260
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8IVT5"
FT MOD_RES 297
FT /note="Phosphoserine; by MARK3"
FT /evidence="ECO:0000269|PubMed:11741534"
FT MOD_RES 320
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 337
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8IVT5"
FT MOD_RES 392
FT /note="Phosphoserine; by MARK3"
FT /evidence="ECO:0000269|PubMed:11741534,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 411
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8IVT5"
FT MOD_RES 518
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 838
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:21102438"
FT VAR_SEQ 474
FT /note="P -> PAAYFIHHRQQFIFP (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_012232"
FT VAR_SEQ 848..873
FT /note="DINSSKVMPRFERFGLGTLESGNPKM -> EL (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_012233"
FT MUTAGEN 56..57
FT /note="LR->GS: No effect on the interaction with MAP2K1,
FT MAP2K2 and YWHAE. Abolishes interaction with BRAF.
FT Abolishes location at membrane ruffles."
FT /evidence="ECO:0000269|PubMed:10409742,
FT ECO:0000269|PubMed:23250398"
FT MUTAGEN 71
FT /note="I->A: Impairs interaction with BRAF and association
FT with membrane ruffles; when associated with A-78."
FT /evidence="ECO:0000269|PubMed:23250398"
FT MUTAGEN 78
FT /note="L->A: Impairs interaction with BRAF and association
FT with membrane ruffles; when associated with A-78."
FT /evidence="ECO:0000269|PubMed:23250398"
FT MUTAGEN 297
FT /note="S->A: Constitutive targeting to the plasma membrane;
FT when associated with A-392."
FT /evidence="ECO:0000269|PubMed:11741534"
FT MUTAGEN 392
FT /note="S->A: Constitutive targeting to the plasma membrane;
FT when associated with A-297."
FT /evidence="ECO:0000269|PubMed:11741534"
FT MUTAGEN 397
FT /note="I->A: Decrease in MARK3 binding; when associated
FT with A-401."
FT /evidence="ECO:0000269|PubMed:11741534"
FT MUTAGEN 401
FT /note="V->A: Decrease in MARK3 binding; when associated
FT with A-397."
FT /evidence="ECO:0000269|PubMed:11741534"
FT MUTAGEN 572
FT /note="G->E: Decrease in MEK binding."
FT /evidence="ECO:0000269|PubMed:10891492"
FT MUTAGEN 580
FT /note="G->E: Partial decrease in MAP2K1 and MAP2K2 binding.
FT No effect on the interaction with YWHAE."
FT /evidence="ECO:0000269|PubMed:10409742"
FT MUTAGEN 587
FT /note="A->F: Loss of ATP binding and reduces MAPK1 and
FT MAPK3 phosphorylation levels. Loss of kinase activity
FT towards MAP2K1 in vitro. Abnormal constitutive interaction
FT with CRAF. No effect on the interaction with BRAF and
FT MAP2K1."
FT /evidence="ECO:0000269|PubMed:21441104"
FT MUTAGEN 587
FT /note="A->V: No effect on ATP binding and MAPK1 and MAPK3
FT phosphorylation levels. No effect on the interaction with
FT MAP2K1."
FT /evidence="ECO:0000269|PubMed:21441104"
FT MUTAGEN 589
FT /note="R->M: Severe decrease in MAP2K1 and MAP2K2 binding.
FT No effect on the interaction with YWHAE."
FT /evidence="ECO:0000269|PubMed:10409742,
FT ECO:0000269|PubMed:10891492"
FT MUTAGEN 615
FT /note="R->H: Severe decrease in MAP2K1 and MAP2K2 binding.
FT No effect on the interaction with YWHAE."
FT /evidence="ECO:0000269|PubMed:10409742,
FT ECO:0000269|PubMed:10891492"
FT MUTAGEN 700
FT /note="D->V: Decrease in MEK binding."
FT /evidence="ECO:0000269|PubMed:10891492"
FT MUTAGEN 809
FT /note="C->Y: Associates almost exclusively with the
FT membrane. Loss of MAP2K2 and MAP2K2 binding and recruitment
FT to the membrane. Loss of MAP kinase-mediated inhibition of
FT ELK1 phosphorylation. No effect on the interaction with
FT YWHAE."
FT /evidence="ECO:0000269|PubMed:10409742,
FT ECO:0000269|PubMed:10891492"
FT MUTAGEN 838
FT /note="S->A: Abolishes one phosphorylation site. Decreases
FT phosphorylation by PKA."
FT /evidence="ECO:0000269|PubMed:21102438"
FT TURN 30..32
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 33..36
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 37..39
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 47..58
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 65..82
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 83..85
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 88..90
FT /evidence="ECO:0007829|PDB:2LPE"
FT TURN 94..96
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 101..103
FT /evidence="ECO:0007829|PDB:2LPE"
FT TURN 108..110
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 111..114
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 118..121
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 130..133
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 138..146
FT /evidence="ECO:0007829|PDB:2LPE"
FT TURN 147..149
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 153..162
FT /evidence="ECO:0007829|PDB:2LPE"
FT HELIX 163..167
FT /evidence="ECO:0007829|PDB:2LPE"
FT STRAND 336..339
FT /evidence="ECO:0007829|PDB:1KBE"
FT STRAND 347..349
FT /evidence="ECO:0007829|PDB:1KBE"
FT STRAND 356..359
FT /evidence="ECO:0007829|PDB:1KBE"
FT TURN 360..363
FT /evidence="ECO:0007829|PDB:1KBE"
FT STRAND 364..369
FT /evidence="ECO:0007829|PDB:1KBE"
FT TURN 371..373
FT /evidence="ECO:0007829|PDB:1KBE"
SQ SEQUENCE 873 AA; 96755 MW; EAEEB23FAE715D94 CRC64;
MDRAALRAAA MGEKKEGGGG GAAADGGAGA AVSRALQQCG QLQKLIDISI GSLRGLRTKC
SVSNDLTQQE IRTLEAKLVK YICKQQQSKL SVTPSDRTAE LNSYPRFSDW LYIFNVRPEV
VQEIPQELTL DALLEMDEAK AKEMLRRWGA STEECSRLQQ ALTCLRKVTG LGGEHKMDSG
WSSTDARDSS LGPPMDMLSS LGRAGASTQG PRSISVSALP ASDSPVPGLS EGLSDSCIPL
HTSGRLTPRA LHSFITPPTT PQLRRHAKLK PPRTPPPPSR KVFQLLPSFP TLTRSKSHES
QLGNRIDDVT PMKFELPHGS PQLVRRDIGL SVTHRFSTKS WLSQVCNVCQ KSMIFGVKCK
HCRLKCHNKC TKEAPACRIT FLPLARLRRT ESVPSDINNP VDRAAEPHFG TLPKALTKKE
HPPAMNLDSS SNPSSTTSST PSSPAPFLTS SNPSSATTPP NPSPGQRDSR FSFPDISACS
QAAPLSSTAD STRLDDQPKT DVLGVHEAEA EEPEAGKSEA EDDEEDEVDD LPSSRRPWRG
PISRKASQTS VYLQEWDIPF EQVELGEPIG QGRWGRVHRG RWHGEVAIRL LEMDGHNQDH
LKLFKKEVMN YRQTRHENVV LFMGACMNPP HLAIITSFCK GRTLHSFVRD PKTSLDINKT
RQIAQEIIKG MGYLHAKGIV HKDLKSKNVF YDNGKVVITD FGLFGISGVV REERRENQLK
LSHDWLCYLA PEIVREMIPG RDEDQLPFSK AADVYAFGTV WYELQARDWP FKHQPAEALI
WQIGSGEGVR RVLASVSLGK EVGEILSACW AFDLQERPSF SLLMDMLERL PKLNRRLSHP
GHFWKSADIN SSKVMPRFER FGLGTLESGN PKM
