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Q5TCX8 (M3KL4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 99. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase MLK4

EC=2.7.11.25
Alternative name(s):
Mixed lineage kinase 4
Gene names
Name:MLK4
Synonyms:KIAA1804
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1036 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Negative regulator of TLR4 signaling. Does not activate JNK1/MAPK8 pathway, p38/MAPK14, nor ERK2/MAPK1 pathways. Ref.11

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity. UniProtKB P80192

Enzyme regulation

Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation By similarity. UniProtKB Q16584

Subunit structure

Homodimer By similarity. Interacts with TLR4. Ref.11 UniProtKB Q16584

Post-translational modification

Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation By similarity. UniProtKB Q16584

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Contains 1 protein kinase domain.

Contains 1 SH3 domain.

Sequence caution

The sequence BAB47433.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 Ref.6 (identifier: Q5TCX8-1)

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.
Isoform 2 Ref.6 (identifier: Q5TCX8-2)

Also known as: MLK4alpha;

The sequence of this isoform differs from the canonical sequence as follows:
     559-570: LTSDESNKTWGR → CELSALPRGLLC
     571-1036: Missing.
Isoform 3 Ref.3 (identifier: Q5TCX8-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-554: Missing.
     555-559: RAIQL → MFFLVT
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 10361036Mitogen-activated protein kinase kinase kinase MLK4
PRO_0000086268

Regions

Domain38 – 10265SH3
Domain124 – 401278Protein kinase
Nucleotide binding130 – 1389ATP By similarity UniProtKB Q02779
Region425 – 44622Leucine-zipper 1
Region460 – 48122Leucine-zipper 2
Compositional bias15 – 3723Ser-rich

Sites

Active site2631Proton acceptor By similarity UniProtKB Q02779
Binding site1511ATP By similarity UniProtKB Q02779

Amino acid modifications

Modified residue2991Phosphothreonine; by autocatalysis By similarity UniProtKB Q16584
Modified residue3031Phosphoserine; by autocatalysis and MAP4K1 By similarity UniProtKB Q16584
Modified residue5281Phosphoserine Ref.6 Ref.9 Ref.10
Modified residue5921Phosphothreonine Ref.9
Modified residue6141Phosphoserine Ref.7 Ref.9

Natural variations

Alternative sequence1 – 554554Missing in isoform 3. Ref.2
VSP_051731
Alternative sequence555 – 5595RAIQL → MFFLVT in isoform 3. Ref.3
VSP_051732
Alternative sequence559 – 57012LTSDE…KTWGR → CELSALPRGLLC in isoform 2. Ref.6
VSP_051733
Alternative sequence571 – 1036466Missing in isoform 2. Ref.6
VSP_051734
Natural variant4201D → N. Ref.12
Corresponds to variant rs35465006 [ dbSNP | Ensembl ].
VAR_040729
Natural variant5631E → D. Ref.12
Corresponds to variant rs35758282 [ dbSNP | Ensembl ].
VAR_040730
Natural variant5971S → F. Ref.12
Corresponds to variant rs34984140 [ dbSNP | Ensembl ].
VAR_040731
Natural variant7281V → I. Ref.12
Corresponds to variant rs3795375 [ dbSNP | Ensembl ].
VAR_040732
Natural variant7411E → D. Ref.12
Corresponds to variant rs3795374 [ dbSNP | Ensembl ].
VAR_040733
Natural variant7841C → G. Ref.12
Corresponds to variant rs963981 [ dbSNP | Ensembl ].
VAR_040734
Natural variant8921R → W. Ref.12
Corresponds to variant rs55681416 [ dbSNP | Ensembl ].
VAR_040735
Natural variant9001T → I. Ref.12
Corresponds to variant rs34499091 [ dbSNP | Ensembl ].
VAR_040736
Natural variant9771R → C. Ref.12
Corresponds to variant rs56065162 [ dbSNP | Ensembl ].
VAR_040737
Natural variant9821P → L. Ref.12
Corresponds to variant rs34794284 [ dbSNP | Ensembl ].
VAR_040738

Experimental info

Sequence conflict2741K → E in CAC84639. Ref.1
Sequence conflict2741K → E in CAC84640. Ref.1
Sequence conflict3301Y → C in CAC84639. Ref.1
Sequence conflict3301Y → C in CAC84640. Ref.1
Sequence conflict6871E → G in CAC84640. Ref.1
Sequence conflict7011S → T in CAC84640. Ref.1
Sequence conflict7051T → A in CAC84640. Ref.1
Sequence conflict7811P → S in CAC84640. Ref.1
Sequence conflict8721Q → R in CAC84640. Ref.1
Sequence conflict10021A → V in CAC84640. Ref.1
Sequence conflict10161C → G in CAC84640. Ref.1
Isoform 2:
Sequence conflict5661R → P in CAC84639. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (MLK4beta) [UniParc].

Last modified December 21, 2004. Version 1.
Checksum: 2520984802143069

FASTA1,036113,957
        10         20         30         40         50         60 
MALRGAAGAT DTPVSSAGGA PGGSASSSST SSGGSASAGA GLWAALYDYE ARGEDELSLR 

        70         80         90        100        110        120 
RGQLVEVLSQ DAAVSGDEGW WAGQVQRRLG IFPANYVAPC RPAASPAPPP SRPSSPVHVA 

       130        140        150        160        170        180 
FERLELKELI GAGGFGQVYR ATWQGQEVAV KAARQDPEQD AAAAAESVRR EARLFAMLRH 

       190        200        210        220        230        240 
PNIIELRGVC LQQPHLCLVL EFARGGALNR ALAAANAAPD PRAPGPRRAR RIPPHVLVNW 

       250        260        270        280        290        300 
AVQIARGMLY LHEEAFVPIL HRDLKSSNIL LLEKIEHDDI CNKTLKITDF GLAREWHRTT 

       310        320        330        340        350        360 
KMSTAGTYAW MAPEVIKSSL FSKGSDIWSY GVLLWELLTG EVPYRGIDGL AVAYGVAVNK 

       370        380        390        400        410        420 
LTLPIPSTCP EPFAKLMKEC WQQDPHIRPS FALILEQLTA IEGAVMTEMP QESFHSMQDD 

       430        440        450        460        470        480 
WKLEIQQMFD ELRTKEKELR SREEELTRAA LQQKSQEELL KRREQQLAER EIDVLERELN 

       490        500        510        520        530        540 
ILIFQLNQEK PKVKKRKGKF KRSRLKLKDG HRISLPSDFQ HKITVQASPN LDKRRSLNSS 

       550        560        570        580        590        600 
SSSPPSSPTM MPRLRAIQLT SDESNKTWGR NTVFRQEEFE DVKRNFKKKG CTWGPNSIQM 

       610        620        630        640        650        660 
KDRTDCKERI RPLSDGNSPW STILIKNQKT MPLASLFVDQ PGSCEEPKLS PDGLEHRKPK 

       670        680        690        700        710        720 
QIKLPSQAYI DLPLGKDAQR ENPAEAESWE EAASANAATV SIEMTPTNSL SRSPQRKKTE 

       730        740        750        760        770        780 
SALYGCTVLL ASVALGLDLR ELHKAQAAEE PLPKEEKKKR EGIFQRASKS RRSASPPTSL 

       790        800        810        820        830        840 
PSTCGEASSP PSLPLSSALG ILSTPSFSTK CLLQMDSEDP LVDSAPVTCD SEMLTPDFCP 

       850        860        870        880        890        900 
TAPGSGREPA LMPRLDTDCS VSRNLPSSFL QQTCGNVPYC ASSKHRPSHH RRTMSDGNPT 

       910        920        930        940        950        960 
PTGATIISAT GASALPLCPS PAPHSHLPRE VSPKKHSTVH IVPQRRPASL RSRSDLPQAY 

       970        980        990       1000       1010       1020 
PQTAVSQLAQ TACVVGRPGP HPTQFLAAKE RTKSHVPSLL DADVEGQSRD YTVPLCRMRS 

      1030 
KTSRPSIYEL EKEFLS 

« Hide

Isoform 2 (MLK4alpha) [UniParc].

Checksum: 7D8A39D60DBA84F9
Show »

FASTA57063,040
Isoform 3 [UniParc].

Checksum: B38F2AB9CBA7A614
Show »

FASTA48352,817

References

« Hide 'large scale' references
[1]"MLK4, a new member of mixed lineage kinases."
Kvasha S., Protopopov A., Rynditch A., Zabarovsky E., Kashuba V.
Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
Tissue: Heart.
[2]"Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro."
Nagase T., Nakayama M., Nakajima D., Kikuno R., Ohara O.
DNA Res. 8:85-95(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
Tissue: Brain.
[3]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-528, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[7]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-614, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[8]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-528; THR-592 AND SER-614, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-528, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[11]"MLK4 has negative effect on TLR4 signaling."
Seit-Nebi A., Cheng W., Xu H., Han J.
Cell. Mol. Immunol. 9:27-33(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TLR4.
[12]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASN-420; ASP-563; PHE-597; ILE-728; ASP-741; GLY-784; TRP-892; ILE-900; CYS-977 AND LEU-982.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_115811.2. NM_032435.2.
UniGeneHs.547779.

3D structure databases

ProteinModelPortalQ5TCX8.
SMRQ5TCX8. Positions 42-473.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid124089. 2 interactions.
IntActQ5TCX8. 2 interactions.

PTM databases

PhosphoSiteQ5TCX8.

Polymorphism databases

DMDM71153820.

Proteomic databases

PaxDbQ5TCX8.
PRIDEQ5TCX8.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID84451.
KEGGhsa:84451.
UCSCuc001hvs.1. human. [Q5TCX8-2]
uc001hvt.4. human. [Q5TCX8-1]
uc001hvu.4. human. [Q5TCX8-3]

Organism-specific databases

CTD84451.
GeneCardsGC01P233463.
H-InvDBHIX0001705.
HPAHPA007636.
MIM614793. gene.
neXtProtNX_Q5TCX8.
HUGESearch...

Phylogenomic databases

eggNOGCOG0515.
HOVERGENHBG067662.
InParanoidQ5TCX8.
KOK17534.
OMACEEPKLS.
PhylomeDBQ5TCX8.

Gene expression databases

BgeeQ5TCX8.
GenevestigatorQ5TCX8.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR016231. MAPKKK9/10/11.
IPR015785. MAPKKK_4/9/10/11.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR001452. SH3_domain.
IPR020635. Tyr_kinase_cat_dom.
[Graphical view]
PANTHERPTHR23257:SF87. PTHR23257:SF87. 1 hit.
PfamPF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PIRSFPIRSF000556. MAPKKK9_11. 1 hit.
PRINTSPR00452. SH3DOMAIN.
PR00109. TYRKINASE.
SMARTSM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF50044. SSF50044. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GenomeRNAi84451.
NextBio74235.
PROQ5TCX8.
SOURCESearch...

Entry information

Entry nameM3KL4_HUMAN
AccessionPrimary (citable) accession number: Q5TCX8
Secondary accession number(s): B2RN34 expand/collapse secondary AC list , Q5TCX7, Q5TCX9, Q8WWN1, Q8WWN2, Q96JM1
Entry history
Integrated into UniProtKB/Swiss-Prot: July 19, 2005
Last sequence update: December 21, 2004
Last modified: April 16, 2014
This is version 99 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM