Reviewed, UniProtKB/Swiss-Prot Q5TCX8 (M3KL4_HUMAN)

Names and origin

Protein names

Recommended name:
    Mitogen-activated protein kinase kinase kinase
    EC=2.7.11.25
Alternative name(s):
    Mixed lineage kinase 4

Gene names

Name:	MLK4
Synonyms:	KIAA1804

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1036 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Activates the JUN N-terminal pathway By similarity. UniProtKB Q16584
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. 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.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	activation of JUN kinase activity Inferred from sequence or structural similarity. Source: UniProtKB protein amino acid autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase kinase activity Inferred from electronic annotation. Source: EC protein homodimerization activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 Ref.4 (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.4 (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.
Sequence annotation (Features)
	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
	Sequence conflict	566	1	R → P in CAC84639. Ref.1
Isoform 3 Ref.2 (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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1036	1036	Mitogen-activated protein kinase kinase kinase		PRO_0000086268
Regions
	Domain	38 – 102	65	SH3
	Domain	124 – 401	278	Protein kinase
	Domain	425 – 446	22	Leucine-zipper 1 By similarity UniProtKB Q02779
	Domain	460 – 481	22	Leucine-zipper 2 By similarity UniProtKB Q02779
	Nucleotide binding	130 – 138	9	ATP By similarity UniProtKB Q02779
	Compositional bias	15 – 37	23	Ser-rich
Sites
	Active site	263	1	Proton acceptor By similarity UniProtKB Q02779
	Binding site	151	1	ATP By similarity UniProtKB Q02779
Amino acid modifications
	Modified residue	299	1	Phosphothreonine; by autocatalysis By similarity UniProtKB Q16584
	Modified residue	303	1	Phosphoserine; by autocatalysis and MAP4K1 By similarity UniProtKB Q16584
	Modified residue	514	1	Phosphoserine Ref.4
	Modified residue	528	1	Phosphoserine Ref.4
	Modified residue	547	1	Phosphoserine By similarity UniProtKB Q16584
	Modified residue	614	1	Phosphoserine Ref.4 Ref.5
	Modified residue	732	1	Phosphoserine By similarity UniProtKB Q16584
	Modified residue	806	1	Phosphoserine By similarity UniProtKB Q16584
Natural variations
	Alternative sequence	1 – 554	554	Missing in isoform 3. Ref.2		VSP_051731
	Alternative sequence	555 – 559	5	RAIQL → MFFLVT in isoform 3. Ref.2		VSP_051732
	Alternative sequence	559 – 570	12	LTSDE…KTWGR → CELSALPRGLLC in isoform 2. Ref.4		VSP_051733
	Alternative sequence	571 – 1036	466	Missing in isoform 2. Ref.4		VSP_051734
	Natural variant	420	1	D → N		VAR_040729
	Natural variant	563	1	E → D		VAR_040730
	Natural variant	597	1	S → F		VAR_040731
	Natural variant	728	1	V → I: dbSNP rs3795375. Ref.6		VAR_040732
	Natural variant	741	1	E → D: dbSNP rs3795374. Ref.6		VAR_040733
	Natural variant	784	1	C → G: dbSNP rs963981. Ref.6		VAR_040734
	Natural variant	892	1	R → W		VAR_040735
	Natural variant	900	1	T → I		VAR_040736
	Natural variant	977	1	R → C		VAR_040737
	Natural variant	982	1	P → L		VAR_040738
Experimental info
	Sequence conflict	274	1	K → E in CAC84639. Ref.1
	Sequence conflict	274	1	K → E in CAC84640. Ref.1
	Sequence conflict	330	1	Y → C in CAC84639. Ref.1
	Sequence conflict	330	1	Y → C in CAC84640. Ref.1
	Sequence conflict	687	1	E → G in CAC84640. Ref.1
	Sequence conflict	701	1	S → T in CAC84640. Ref.1
	Sequence conflict	705	1	T → A in CAC84640. Ref.1
	Sequence conflict	781	1	P → S in CAC84640. Ref.1
	Sequence conflict	872	1	Q → R in CAC84640. Ref.1
	Sequence conflict	1002	1	A → V in CAC84640. Ref.1
	Sequence conflict	1016	1	C → G in CAC84640. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (MLK4beta) [UniParc]. Last modified December 21, 2004. Version 1. Checksum: 2520984802143069	FASTA	1,036	113,957
	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
	Isoform 2 (MLK4alpha). Checksum: 7D8A39D60DBA84F9	FASTA	570	63,040
	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 SSSPPSSPTM MPRLRAIQCE LSALPRGLLC
	Isoform 3. Checksum: B38F2AB9CBA7A614	FASTA	483	52,817
	10 20 30 40 50 60 MFFLVTTSDE SNKTWGRNTV FRQEEFEDVK RNFKKKGCTW GPNSIQMKDR TDCKERIRPL 70 80 90 100 110 120 SDGNSPWSTI LIKNQKTMPL ASLFVDQPGS CEEPKLSPDG LEHRKPKQIK LPSQAYIDLP 130 140 150 160 170 180 LGKDAQRENP AEAESWEEAA SANAATVSIE MTPTNSLSRS PQRKKTESAL YGCTVLLASV 190 200 210 220 230 240 ALGLDLRELH KAQAAEEPLP KEEKKKREGI FQRASKSRRS ASPPTSLPST CGEASSPPSL 250 260 270 280 290 300 PLSSALGILS TPSFSTKCLL QMDSEDPLVD SAPVTCDSEM LTPDFCPTAP GSGREPALMP 310 320 330 340 350 360 RLDTDCSVSR NLPSSFLQQT CGNVPYCASS KHRPSHHRRT MSDGNPTPTG ATIISATGAS 370 380 390 400 410 420 ALPLCPSPAP HSHLPREVSP KKHSTVHIVP QRRPASLRSR SDLPQAYPQT AVSQLAQTAC 430 440 450 460 470 480 VVGRPGPHPT QFLAAKERTK SHVPSLLDAD VEGQSRDYTV PLCRMRSKTS RPSIYELEKE FLS

References

	« Hide 'large scale' referencesShow '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: 11347906] [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. , 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: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-514; SER-528 AND SER-614, MASS SPECTROMETRY.
[5]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-614, MASS SPECTROMETRY.
[6]	"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. , 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: 17344846] [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.

Cross-references

Sequence databases
EMBLGenBankDDBJ	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.
IPI	IPI00142487. IPI00607654. IPI00607875.
RefSeq	NP_115811.2.
UniGene	Hs.547779
3D structure databases
HSSP	HSSP built from PDB template 1OEB based on UniProtKB O89100.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q5TCX8. 1 interaction.
STRING	Q5TCX8.
PTM databases
PhosphoSite	Q5TCX8.
Proteomic databases
PRIDE	Q5TCX8.
Genome annotation databases
Ensembl	ENST00000366622; ENSP00000355581; ENSG00000143674; Homo sapiens. [Genome view] ENST00000366623; ENSP00000355582; ENSG00000143674; Homo sapiens. [Genome view] ENST00000366624; ENSP00000355583; ENSG00000143674; Homo sapiens. [Genome view]
GeneID	84451.
KEGG	hsa:84451.
NMPDR	fig|9606.3.peg.3263.
UCSC	uc001hvs.1. human. uc001hvt.2. human. uc001hvu.2. human.
Organism-specific databases
CTD	84451.
GeneCards	GC01P231530.
HPA	HPA007636.
HUGE	Search...
Phylogenomic databases
HOGENOM	Q5TCX8.
HOVERGEN	Q5TCX8.
OMA	RPSIYEL.
Enzyme and pathway databases
BRENDA	2.7.11.25. 247.
Gene expression databases
ArrayExpress	Q5TCX8.
Bgee	Q5TCX8.
Genevestigator	Q5TCX8.
GermOnline	ENSG00000143674. Homo sapiens.
Family and domain databases
InterPro	IPR015785. MAPKKK-like. IPR016231. MAPKKK9/10/11. IPR000719. Prot_kinase_core. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_pkinase-rel. IPR008271. Ser_thr_pkin_AS. IPR001452. SH3_domain. IPR020473. SH3_region. IPR001245. Tyr_pkinase. [Graphical view]
PANTHER	PTHR23257:SF87. MAPKKK-like. 1 hit.
Pfam	PF00069. Pkinase. 1 hit. PF00018. SH3_1. 1 hit. [Graphical view]
PIRSF	PIRSF000556. MAPKKK9_11. 1 hit.
PRINTS	PR00452. SH3DOMAIN. PR00109. TYRKINASE.
ProDom	PD000001. Prot_kinase. 1 hit. PD000066. SH3. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00326. SH3. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. PS50002. SH3. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	74235.

Entry information

Entry name

M3KL4_HUMAN

Accession

Primary (citable) accession number: Q5TCX8
Secondary accession number(s): Q5TCX7 , Q5TCX9, Q8WWN1, Q8WWN2, Q96JM1

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2005
Last sequence update:	December 21, 2004
Last modified:	November 3, 2009
This is version 53 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.