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Protein

Mitogen-activated protein kinase kinase kinase MLK4

Gene

MLK4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

Enzyme 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

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS07095-MONOMER.

Names & Taxonomyi

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

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

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 MLK4Add 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 residuei592PhosphothreonineBy similarity1
Modified residuei614PhosphoserineBy similarity1

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.

PTM databases

iPTMnetiQ5TCX8.
PhosphoSitePlusiQ5TCX8.

Expressioni

Gene expression databases

BgeeiENSG00000143674.
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. 11 interactors.
IntActiQ5TCX8. 10 interactors.
STRINGi9606.ENSP00000355583.

Structurei

Secondary structure

11036
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi121 – 123Combined sources3
Beta strandi125 – 129Combined sources5
Beta strandi138 – 143Combined sources6
Beta strandi146 – 152Combined sources7
Helixi165 – 175Combined sources11
Beta strandi186 – 190Combined sources5
Beta strandi197 – 201Combined sources5
Helixi208 – 212Combined sources5
Helixi234 – 252Combined sources19
Beta strandi255 – 257Combined sources3
Helixi266 – 268Combined sources3
Beta strandi269 – 273Combined sources5
Beta strandi285 – 287Combined sources3
Helixi313 – 316Combined sources4
Helixi323 – 339Combined sources17
Turni343 – 346Combined sources4
Helixi349 – 357Combined sources9
Helixi373 – 380Combined sources8
Helixi391 – 399Combined sources9
Helixi411 – 436Combined sources26

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...

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

Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 SH3 domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, SH3 domain

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118807.
HOVERGENiHBG067662.
InParanoidiQ5TCX8.
KOiK17534.
OMAiPWSTILI.
OrthoDBiEOG091G0JNI.
PhylomeDBiQ5TCX8.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR016231. MLK1/MLK2/MLK4.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR001452. SH3_domain.
[Graphical view]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF14604. SH3_9. 1 hit.
[Graphical view]
PIRSFiPIRSF000556. MAPKKK9_11. 1 hit.
PRINTSiPR00452. SH3DOMAIN.
PR00109. TYRKINASE.
SMARTiSM00220. S_TKc. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]

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:December 21, 2004 - v1
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 → MFFLVT

Note: No experimental confirmation available.Curated
Show »
Length:483
Mass (Da):52,817
Checksum:iB38F2AB9CBA7A614
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 → N.1 PublicationCorresponds to variant rs35465006dbSNPEnsembl.1
Natural variantiVAR_040730563E → D.1 PublicationCorresponds to variant rs35758282dbSNPEnsembl.1
Natural variantiVAR_040731597S → F.1 PublicationCorresponds to variant rs34984140dbSNPEnsembl.1
Natural variantiVAR_040732728V → I.1 PublicationCorresponds to variant rs3795375dbSNPEnsembl.1
Natural variantiVAR_040733741E → D.1 PublicationCorresponds to variant rs3795374dbSNPEnsembl.1
Natural variantiVAR_040734784C → G.1 PublicationCorresponds to variant rs963981dbSNPEnsembl.1
Natural variantiVAR_040735892R → W.1 PublicationCorresponds to variant rs55681416dbSNPEnsembl.1
Natural variantiVAR_040736900T → I.1 PublicationCorresponds to variant rs34499091dbSNPEnsembl.1
Natural variantiVAR_040737977R → C.1 PublicationCorresponds to variant rs56065162dbSNPEnsembl.1
Natural variantiVAR_040738982P → L.1 PublicationCorresponds to variant rs34794284dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0517311 – 554Missing in isoform 3. 1 PublicationAdd BLAST554
Alternative sequenceiVSP_051732555 – 559RAIQL → MFFLVT 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. Translation: CAI23045.1.
AL133380 Genomic DNA. Translation: CAI23046.1.
AL133380 Genomic DNA. Translation: CAI23047.1.
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

GeneIDi84451.
KEGGihsa:84451.
UCSCiuc001hvt.4. human. [Q5TCX8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

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. Translation: CAI23045.1.
AL133380 Genomic DNA. Translation: CAI23046.1.
AL133380 Genomic DNA. Translation: CAI23047.1.
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. 11 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.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi84451.
KEGGihsa:84451.
UCSCiuc001hvt.4. human. [Q5TCX8-1]

Organism-specific databases

CTDi84451.
DisGeNETi84451.
GeneCardsiKIAA1804.
H-InvDBHIX0001705.
HPAiHPA007636.
MIMi614793. gene.
neXtProtiNX_Q5TCX8.
OpenTargetsiENSG00000143674.
HUGEiSearch...

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000118807.
HOVERGENiHBG067662.
InParanoidiQ5TCX8.
KOiK17534.
OMAiPWSTILI.
OrthoDBiEOG091G0JNI.
PhylomeDBiQ5TCX8.

Enzyme and pathway databases

BioCyciZFISH:HS07095-MONOMER.

Miscellaneous databases

ChiTaRSiKIAA1804. human.
GenomeRNAii84451.
PROiQ5TCX8.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000143674.
ExpressionAtlasiQ5TCX8. baseline and differential.
GenevisibleiQ5TCX8. HS.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR016231. MLK1/MLK2/MLK4.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR001452. SH3_domain.
[Graphical view]
PfamiPF07714. Pkinase_Tyr. 1 hit.
PF14604. SH3_9. 1 hit.
[Graphical view]
PIRSFiPIRSF000556. MAPKKK9_11. 1 hit.
PRINTSiPR00452. SH3DOMAIN.
PR00109. TYRKINASE.
SMARTiSM00220. S_TKc. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiM3KL4_HUMAN
AccessioniPrimary (citable) accession number: Q5TCX8
Secondary accession number(s): B2RN34
, Q5TCX7, Q5TCX9, Q8WWN1, Q8WWN2, Q96JM1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 19, 2005
Last sequence update: December 21, 2004
Last modified: November 30, 2016
This is version 126 of the entry and version 1 of the sequence. [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. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.