M3K21_MOUSE
ID M3K21_MOUSE Reviewed; 1002 AA.
AC Q8VDG6; Q5DTU6; Q811F5;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT 11-SEP-2007, sequence version 2.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 21;
DE EC=2.7.11.25;
DE AltName: Full=Mitogen-activated protein kinase kinase kinase MLK4;
DE AltName: Full=Mixed lineage kinase 4;
GN Name=Map3k21; Synonyms=Kiaa1804, Mlk4;
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:0000312|EMBL:BAD90469.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Embryonic intestine {ECO:0000312|EMBL:BAD90469.1};
RA Okazaki N., Kikuno R.F., Ohara R., Inamoto S., Nagase T., Ohara O.,
RA Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene. The
RT complete nucleotide sequences of mouse KIAA-homologous cDNAs identified by
RT screening of terminal sequences of cDNA clones randomly sampled from size-
RT fractionated libraries.";
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [2] {ECO:0000312|EMBL:AAH21891.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N {ECO:0000312|EMBL:AAH21891.1};
RC TISSUE=Mammary gland {ECO:0000312|EMBL:AAH21891.1};
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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-527; SER-531; THR-576 AND
RP SER-598, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, and Testis;
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).
CC -!- FUNCTION: Negative regulator of TLR4 signaling. Does not activate
CC JNK1/MAPK8 pathway, p38/MAPK14, nor ERK2/MAPK1 pathways (By
CC similarity). {ECO:0000250}.
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=2.7.11.25;
CC Evidence={ECO:0000250|UniProtKB:P80192};
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=2.7.11.25; Evidence={ECO:0000250|UniProtKB:P80192};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P80192};
CC -!- ACTIVITY REGULATION: Homodimerization via the leucine zipper domains is
CC required for autophosphorylation and subsequent activation.
CC {ECO:0000250|UniProtKB:P80192}.
CC -!- SUBUNIT: Homodimer. Interacts with TLR4. {ECO:0000250}.
CC -!- PTM: Autophosphorylation on serine and threonine residues within the
CC activation loop plays a role in enzyme activation.
CC {ECO:0000250|UniProtKB:P80192}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000250|UniProtKB:P80192}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD90469.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAD90469.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK220424; BAD90469.1; ALT_SEQ; mRNA.
DR EMBL; BC021891; AAH21891.1; -; mRNA.
DR EMBL; BC046448; AAH46448.1; -; mRNA.
DR CCDS; CCDS40519.1; -.
DR RefSeq; NP_663583.2; NM_145608.2.
DR AlphaFoldDB; Q8VDG6; -.
DR SMR; Q8VDG6; -.
DR STRING; 10090.ENSMUSP00000034316; -.
DR iPTMnet; Q8VDG6; -.
DR PhosphoSitePlus; Q8VDG6; -.
DR MaxQB; Q8VDG6; -.
DR PaxDb; Q8VDG6; -.
DR PeptideAtlas; Q8VDG6; -.
DR PRIDE; Q8VDG6; -.
DR ProteomicsDB; 252698; -.
DR Antibodypedia; 2080; 230 antibodies from 30 providers.
DR DNASU; 234878; -.
DR Ensembl; ENSMUST00000034316; ENSMUSP00000034316; ENSMUSG00000031853.
DR GeneID; 234878; -.
DR KEGG; mmu:234878; -.
DR UCSC; uc009nyq.1; mouse.
DR CTD; 84451; -.
DR MGI; MGI:2385307; Map3k21.
DR VEuPathDB; HostDB:ENSMUSG00000031853; -.
DR eggNOG; KOG0192; Eukaryota.
DR GeneTree; ENSGT00940000159629; -.
DR HOGENOM; CLU_000288_7_14_1; -.
DR InParanoid; Q8VDG6; -.
DR OMA; KTESALC; -.
DR OrthoDB; 115270at2759; -.
DR PhylomeDB; Q8VDG6; -.
DR TreeFam; TF105118; -.
DR BioGRID-ORCS; 234878; 3 hits in 70 CRISPR screens.
DR ChiTaRS; Map3k21; mouse.
DR PRO; PR:Q8VDG6; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q8VDG6; protein.
DR Bgee; ENSMUSG00000031853; Expressed in ureteric bud tip and 77 other tissues.
DR Genevisible; Q8VDG6; MM.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004706; F:JUN kinase kinase kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR016231; MLK1-4.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF14604; SH3_9; 1.
DR PIRSF; PIRSF000556; MAPKKK9_11; 1.
DR PRINTS; PR00452; SH3DOMAIN.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00220; S_TKc; 1.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Kinase; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Repeat; Serine/threonine-protein kinase; SH3 domain;
KW Transferase.
FT CHAIN 1..1002
FT /note="Mitogen-activated protein kinase kinase kinase 21"
FT /id="PRO_0000302761"
FT DOMAIN 24..88
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 110..390
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..26
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 409..430
FT /note="Leucine-zipper 1"
FT REGION 444..466
FT /note="Leucine-zipper 2"
FT REGION 508..531
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 574..604
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 640..689
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 721..778
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 797..823
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 878..899
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 508..527
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 659..676
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 741..778
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 247
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT ProRule:PRU10027"
FT BINDING 116..124
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 137
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 283
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P80192"
FT MOD_RES 287
FT /note="Phosphoserine; by autocatalysis and MAP4K1"
FT /evidence="ECO:0000250|UniProtKB:P80192"
FT MOD_RES 512
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5TCX8"
FT MOD_RES 527
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 531
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 576
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 598
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CONFLICT 411
FT /note="Missing (in Ref. 2; AAH21891)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1002 AA; 110112 MW; C4E706833A578C78 CRC64;
MALPVAEGTA DTPLSPARDD SGSTSSGMWA ALYDYEARGE DELSLRRGQL VEVLSQDAAV
SGDEGWWAGQ VQRRLGIFPA SYVAPCGPVP PPAPPPPRPC SPVHVDFERL ELKELIGAGG
FGQVYRATWQ GQEVAVKAAR RDPEQDAAAA AESVRREARL FAMLRHPNII QLRGVCLRQP
HLCLVLEFAR GGALNRALAA AASDPRAPGP RRARRIPPQV LVNWAVQIAR GMLYLHEEAV
VPILHRDLKS SNILLLEKIE HDDICNKTLK ITDFGLAREW HRTTRMSAAG TYAWMAPEVI
RSSLFSKGSD IWSYGVLLWE LLTGEVPYRG IDGLAVAYGV AVNKLTLPIP STCPEPFAKL
MKECWEQDPH IRPSFALILQ QLTAIEEAVL TNMPQESFHS MQEDWKLEIQ QMFSELRTKE
KELRSREEEL SRAALQQKSQ ELLLRRREQQ LAEREIDVLE RELNVLIFQL SQEAPHVKKR
KGRFRRGRLR LKDGHRISLP SDFQHKITVQ ASPTLDKRRS SDSGLCSPPG SPLMLPRLRA
IQLTSDENNK TRGRNMVFRQ EDFEDVKRSF KKKGCTWGPS SVQTKERPEG RERVRPLSDG
NSPWSSLLIK SQKTTPLASL FVDQPGSCEE QKLVPEGLEH RKPKQTKFPG QAHVGLPLCK
DSQREDSSEA ESREEGSPKG SPVNNVGAPM LRKKTESALC ECGMLLASMA LGLDVRKLHG
AQAPAKPSPK MEKKEEGALQ PASRCQSSPS SLLRQPSAGR APSGGSTLLL PSAPSHSSKS
SLSMKCLLQA GKEESSLGNA RDLCGPTTLT PDPGSAAPES GCELIPGLRP KTDYGVLRSM
PHAILEQTGE RLPGCAIVGD KGCHHMQMGS EETPLWLQSA PEDSGLPHSP SPGPQRDLAS
QASLVKPEGV LGECQACPAL PQRPHTASVR TTSPPTWVCD KDHQVPALAC LLGAQERSRC
QTPSLLDASI EGQKKDCAMP LCRVKSVMCQ PSIYALEKDF LT
