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Protein

Mitogen-activated protein kinase kinase kinase 21

Gene

MAP3K21

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Negative regulator of TLR4 signaling. Does not activate JNK1/MAPK8 pathway, p38/MAPK14, nor ERK2/MAPK1 pathways.1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.Curated

Cofactori

Mg2+By similarity

Activity regulationi

Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei151ATPPROSITE-ProRule annotationBy similarity1
Active sitei263Proton acceptorPROSITE-ProRule annotationBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi130 – 138ATPPROSITE-ProRule annotationBy similarity9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase kinase kinase 21 (EC:2.7.11.25)
Alternative name(s):
Mitogen-activated protein kinase kinase kinase MLK4
Mixed lineage kinase 4
Gene namesi
Name:MAP3K21Imported
Synonyms:KIAA1804Imported, MLK41 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000143674.10
HGNCiHGNC:29798 MAP3K21
MIMi614793 gene
neXtProtiNX_Q5TCX8

Subcellular locationi

Pathology & Biotechi

Organism-specific databases

DisGeNETi84451
OpenTargetsiENSG00000143674

Chemistry databases

ChEMBLiCHEMBL3627584

Polymorphism and mutation databases

BioMutaiMLK4
DMDMi71153820

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862681 – 1036Mitogen-activated protein kinase kinase kinase 21Add BLAST1036

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei299Phosphothreonine; by autocatalysisBy similarity1
Modified residuei303Phosphoserine; by autocatalysis and MAP4K1By similarity1
Modified residuei528PhosphoserineCombined sources1
Modified residuei543PhosphoserineBy similarity1
Modified residuei547PhosphoserineBy similarity1
Modified residuei592PhosphothreonineCombined sources1
Modified residuei614PhosphoserineCombined sources1

Post-translational modificationi

Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ5TCX8
MaxQBiQ5TCX8
PaxDbiQ5TCX8
PeptideAtlasiQ5TCX8
PRIDEiQ5TCX8
ProteomicsDBi64992
64993 [Q5TCX8-2]
64994 [Q5TCX8-3]

PTM databases

iPTMnetiQ5TCX8
PhosphoSitePlusiQ5TCX8

Expressioni

Gene expression databases

BgeeiENSG00000143674 Expressed in 144 organ(s), highest expression level in pancreas
ExpressionAtlasiQ5TCX8 baseline and differential
GenevisibleiQ5TCX8 HS

Organism-specific databases

HPAiHPA007636

Interactioni

Subunit structurei

Homodimer (By similarity). Interacts with TLR4.By similarity1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
CHUKO151112EBI-1057380,EBI-81249

GO - Molecular functioni

Protein-protein interaction databases

BioGridi124089, 61 interactors
IntActiQ5TCX8, 10 interactors
STRINGi9606.ENSP00000355583

Structurei

Secondary structure

11036
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ5TCX8
SMRiQ5TCX8
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini38 – 102SH3PROSITE-ProRule annotationAdd BLAST65
Domaini124 – 401Protein kinasePROSITE-ProRule annotationAdd BLAST278

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni425 – 446Leucine-zipper 1Add BLAST22
Regioni460 – 481Leucine-zipper 2Add BLAST22

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi15 – 37Ser-richSequence analysisAdd BLAST23

Sequence similaritiesi

Keywords - Domaini

Repeat, SH3 domain

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00930000150812
HOVERGENiHBG067662
InParanoidiQ5TCX8
KOiK17534
OMAiDESNRTW
OrthoDBiEOG091G0JNI
PhylomeDBiQ5TCX8

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR016231 MLK1-4
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
PF14604 SH3_9, 1 hit
PIRSFiPIRSF000556 MAPKKK9_11, 1 hit
PRINTSiPR00452 SH3DOMAIN
PR00109 TYRKINASE
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SM00326 SH3, 1 hit
SUPFAMiSSF50044 SSF50044, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
PS50002 SH3, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket
Isoform 11 Publication (identifier: Q5TCX8-1) [UniParc]FASTAAdd to basket
Also known as: MLK4beta

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MALRGAAGAT DTPVSSAGGA PGGSASSSST SSGGSASAGA GLWAALYDYE
60 70 80 90 100
ARGEDELSLR RGQLVEVLSQ DAAVSGDEGW WAGQVQRRLG IFPANYVAPC
110 120 130 140 150
RPAASPAPPP SRPSSPVHVA FERLELKELI GAGGFGQVYR ATWQGQEVAV
160 170 180 190 200
KAARQDPEQD AAAAAESVRR EARLFAMLRH PNIIELRGVC LQQPHLCLVL
210 220 230 240 250
EFARGGALNR ALAAANAAPD PRAPGPRRAR RIPPHVLVNW AVQIARGMLY
260 270 280 290 300
LHEEAFVPIL HRDLKSSNIL LLEKIEHDDI CNKTLKITDF GLAREWHRTT
310 320 330 340 350
KMSTAGTYAW MAPEVIKSSL FSKGSDIWSY GVLLWELLTG EVPYRGIDGL
360 370 380 390 400
AVAYGVAVNK LTLPIPSTCP EPFAKLMKEC WQQDPHIRPS FALILEQLTA
410 420 430 440 450
IEGAVMTEMP QESFHSMQDD WKLEIQQMFD ELRTKEKELR SREEELTRAA
460 470 480 490 500
LQQKSQEELL KRREQQLAER EIDVLERELN ILIFQLNQEK PKVKKRKGKF
510 520 530 540 550
KRSRLKLKDG HRISLPSDFQ HKITVQASPN LDKRRSLNSS SSSPPSSPTM
560 570 580 590 600
MPRLRAIQLT SDESNKTWGR NTVFRQEEFE DVKRNFKKKG CTWGPNSIQM
610 620 630 640 650
KDRTDCKERI RPLSDGNSPW STILIKNQKT MPLASLFVDQ PGSCEEPKLS
660 670 680 690 700
PDGLEHRKPK QIKLPSQAYI DLPLGKDAQR ENPAEAESWE EAASANAATV
710 720 730 740 750
SIEMTPTNSL SRSPQRKKTE SALYGCTVLL ASVALGLDLR ELHKAQAAEE
760 770 780 790 800
PLPKEEKKKR EGIFQRASKS RRSASPPTSL PSTCGEASSP PSLPLSSALG
810 820 830 840 850
ILSTPSFSTK CLLQMDSEDP LVDSAPVTCD SEMLTPDFCP TAPGSGREPA
860 870 880 890 900
LMPRLDTDCS VSRNLPSSFL QQTCGNVPYC ASSKHRPSHH RRTMSDGNPT
910 920 930 940 950
PTGATIISAT GASALPLCPS PAPHSHLPRE VSPKKHSTVH IVPQRRPASL
960 970 980 990 1000
RSRSDLPQAY PQTAVSQLAQ TACVVGRPGP HPTQFLAAKE RTKSHVPSLL
1010 1020 1030
DADVEGQSRD YTVPLCRMRS KTSRPSIYEL EKEFLS
Length:1,036
Mass (Da):113,957
Last modified:March 28, 2018 - v3
Checksum:i2520984802143069
GO
Isoform 21 Publication (identifier: Q5TCX8-2) [UniParc]FASTAAdd to basket
Also known as: MLK4alpha

The sequence of this isoform differs from the canonical sequence as follows:
     559-570: LTSDESNKTWGR → CELSALPRGLLC
     571-1036: Missing.

Show »
Length:570
Mass (Da):63,040
Checksum:i7D8A39D60DBA84F9
GO
Isoform 3 (identifier: Q5TCX8-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-554: Missing.
     555-559: RAIQL → MFFLV

Note: No experimental confirmation available.Curated
Show »
Length:482
Mass (Da):52,716
Checksum:i49E1E8D8F81ECAAA
GO

Sequence cautioni

The sequence BAB47433 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti274K → E in CAC84639 (Ref. 1) Curated1
Sequence conflicti274K → E in CAC84640 (Ref. 1) Curated1
Sequence conflicti330Y → C in CAC84639 (Ref. 1) Curated1
Sequence conflicti330Y → C in CAC84640 (Ref. 1) Curated1
Sequence conflicti687E → G in CAC84640 (Ref. 1) Curated1
Sequence conflicti701S → T in CAC84640 (Ref. 1) Curated1
Sequence conflicti705T → A in CAC84640 (Ref. 1) Curated1
Sequence conflicti781P → S in CAC84640 (Ref. 1) Curated1
Sequence conflicti872Q → R in CAC84640 (Ref. 1) Curated1
Sequence conflicti1002A → V in CAC84640 (Ref. 1) Curated1
Sequence conflicti1016C → G in CAC84640 (Ref. 1) Curated1
Isoform 21 Publication (identifier: Q5TCX8-2)
Sequence conflicti566R → P in CAC84639 (Ref. 1) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040729420D → N1 PublicationCorresponds to variant dbSNP:rs35465006Ensembl.1
Natural variantiVAR_040730563E → D1 PublicationCorresponds to variant dbSNP:rs35758282Ensembl.1
Natural variantiVAR_040731597S → F1 PublicationCorresponds to variant dbSNP:rs34984140Ensembl.1
Natural variantiVAR_040732728V → I1 PublicationCorresponds to variant dbSNP:rs3795375Ensembl.1
Natural variantiVAR_040733741E → D1 PublicationCorresponds to variant dbSNP:rs3795374Ensembl.1
Natural variantiVAR_040734784C → G1 PublicationCorresponds to variant dbSNP:rs963981Ensembl.1
Natural variantiVAR_040735892R → W1 PublicationCorresponds to variant dbSNP:rs55681416Ensembl.1
Natural variantiVAR_040736900T → I1 PublicationCorresponds to variant dbSNP:rs34499091Ensembl.1
Natural variantiVAR_040737977R → C1 PublicationCorresponds to variant dbSNP:rs56065162Ensembl.1
Natural variantiVAR_040738982P → L1 PublicationCorresponds to variant dbSNP:rs34794284Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0517311 – 554Missing in isoform 3. 1 PublicationAdd BLAST554
Alternative sequenceiVSP_051732555 – 559RAIQL → MFFLV in isoform 3. 1 Publication5
Alternative sequenceiVSP_051733559 – 570LTSDE…KTWGR → CELSALPRGLLC in isoform 2. 1 PublicationAdd BLAST12
Alternative sequenceiVSP_051734571 – 1036Missing in isoform 2. 1 PublicationAdd BLAST466

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ311797 mRNA Translation: CAC84639.1
AJ311798 mRNA Translation: CAC84640.1
AB058707 mRNA Translation: BAB47433.1 Different initiation.
AL133380 Genomic DNA No translation available.
CH471098 Genomic DNA Translation: EAW69988.1
BC136648 mRNA Translation: AAI36649.1
BC136649 mRNA Translation: AAI36650.1
CCDSiCCDS1598.1 [Q5TCX8-1]
RefSeqiNP_115811.2, NM_032435.2 [Q5TCX8-1]
UniGeneiHs.547779

Genome annotation databases

EnsembliENST00000366622; ENSP00000355581; ENSG00000143674 [Q5TCX8-3]
ENST00000366623; ENSP00000355582; ENSG00000143674 [Q5TCX8-2]
ENST00000366624; ENSP00000355583; ENSG00000143674 [Q5TCX8-1]
GeneIDi84451
KEGGihsa:84451
UCSCiuc001hvt.4 human [Q5TCX8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ311797 mRNA Translation: CAC84639.1
AJ311798 mRNA Translation: CAC84640.1
AB058707 mRNA Translation: BAB47433.1 Different initiation.
AL133380 Genomic DNA No translation available.
CH471098 Genomic DNA Translation: EAW69988.1
BC136648 mRNA Translation: AAI36649.1
BC136649 mRNA Translation: AAI36650.1
CCDSiCCDS1598.1 [Q5TCX8-1]
RefSeqiNP_115811.2, NM_032435.2 [Q5TCX8-1]
UniGeneiHs.547779

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4UYAX-ray2.80A115-451[»]
ProteinModelPortaliQ5TCX8
SMRiQ5TCX8
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi124089, 61 interactors
IntActiQ5TCX8, 10 interactors
STRINGi9606.ENSP00000355583

Chemistry databases

ChEMBLiCHEMBL3627584

PTM databases

iPTMnetiQ5TCX8
PhosphoSitePlusiQ5TCX8

Polymorphism and mutation databases

BioMutaiMLK4
DMDMi71153820

Proteomic databases

EPDiQ5TCX8
MaxQBiQ5TCX8
PaxDbiQ5TCX8
PeptideAtlasiQ5TCX8
PRIDEiQ5TCX8
ProteomicsDBi64992
64993 [Q5TCX8-2]
64994 [Q5TCX8-3]

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000366622; ENSP00000355581; ENSG00000143674 [Q5TCX8-3]
ENST00000366623; ENSP00000355582; ENSG00000143674 [Q5TCX8-2]
ENST00000366624; ENSP00000355583; ENSG00000143674 [Q5TCX8-1]
GeneIDi84451
KEGGihsa:84451
UCSCiuc001hvt.4 human [Q5TCX8-1]

Organism-specific databases

CTDi84451
DisGeNETi84451
EuPathDBiHostDB:ENSG00000143674.10
GeneCardsiMAP3K21
H-InvDBiHIX0001705
HGNCiHGNC:29798 MAP3K21
HPAiHPA007636
MIMi614793 gene
neXtProtiNX_Q5TCX8
OpenTargetsiENSG00000143674
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00930000150812
HOVERGENiHBG067662
InParanoidiQ5TCX8
KOiK17534
OMAiDESNRTW
OrthoDBiEOG091G0JNI
PhylomeDBiQ5TCX8

Miscellaneous databases

ChiTaRSiMAP3K21 human
GenomeRNAii84451
PROiPR:Q5TCX8
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000143674 Expressed in 144 organ(s), highest expression level in pancreas
ExpressionAtlasiQ5TCX8 baseline and differential
GenevisibleiQ5TCX8 HS

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR016231 MLK1-4
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
PF14604 SH3_9, 1 hit
PIRSFiPIRSF000556 MAPKKK9_11, 1 hit
PRINTSiPR00452 SH3DOMAIN
PR00109 TYRKINASE
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SM00326 SH3, 1 hit
SUPFAMiSSF50044 SSF50044, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
PS50002 SH3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiM3K21_HUMAN
AccessioniPrimary (citable) accession number: Q5TCX8
Secondary accession number(s): A0A1W2PKR9
, B2RN34, Q5TCX7, Q5TCX9, Q8WWN1, Q8WWN2, Q96JM1, X6R610
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 19, 2005
Last sequence update: March 28, 2018
Last modified: November 7, 2018
This is version 143 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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