Mitogen-activated protein kinase kinase kinase 1

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Reviewed, UniProtKB/Swiss-Prot Q13233 (M3K1_HUMAN)

Last modified November 25, 2008. Version 86. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Mitogen-activated protein kinase kinase kinase 1
    EC=2.7.11.25
Alternative name(s):
    MAPK/ERK kinase kinase 1
      Short name=MEK kinase 1
      Short name=MEKK 1

Gene names

Name:	MAP3K1
Synonyms:	MAPKKK1, MEKK, MEKK1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	1514 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Component of a protein kinase signal transduction cascade. Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4. Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Enzyme regulation	Activated by autophosphorylation on Thr-1402 and Thr-1414 following oligomerization.
Subunit structure	Binds both upstream activators and downstream substrates in multimolecular complexes through its N-terminus. Oligomerizes after binding MAP4K2 or TRAF2. Interacts with AXIN1.
Post-translational modification	Autophosphorylated By similarity.
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 RING-type zinc finger. Contains 1 SWIM-type zinc finger.

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Ontologies

Keywords
Coding sequence diversity	Polymorphism
Domain	Zinc-finger
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding Zinc
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	I-kappaB kinase/NF-kappaB cascade Inferred from Experiment. Source: Reactome
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Non-traceable author statement. Source: UniProtKB MAP kinase kinase kinase activity Ref.2 Non-traceable author statement. Source: UniProtKB magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.2 Inferred from physical interaction. Source: IntAct zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct
IKBKB	O14920	1	EBI-49776,EBI-81266
MAP2K4	P45985	2	EBI-49776,EBI-447868
MAP4K2	Q12851	1	EBI-49776,EBI-49783
TRAF2	Q12933	1	EBI-49776,EBI-355744

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1514

1514

Mitogen-activated protein kinase kinase kinase 1

PRO_0000086240

Regions

Domain

1245 – 1510

266

Protein kinase

Zinc finger

338 – 366

SWIM-type

Zinc finger

443 – 492

RING-type

Nucleotide binding

1251 – 1259

ATP By similarity

Compositional bias

2 – 5

Poly-Ala

Compositional bias

25 – 29

Poly-Gly

Compositional bias

36 – 41

Poly-Ala

Compositional bias

422 – 431

Poly-Ser

Compositional bias

842 – 847

Poly-Ser

Compositional bias

944 – 951

Poly-Thr

Compositional bias

1184 – 1189

Poly-Glu

Compositional bias

1218 – 1221

Poly-Ile

Sites

Active site

1371

Proton acceptor By similarity

Binding site

1274

ATP By similarity

Amino acid modifications

Modified residue

292

Phosphoserine

Modified residue

297

Phosphoserine

Modified residue

300

Phosphoserine

Modified residue

507

Phosphoserine

Modified residue

511

Phosphoserine

Modified residue

657

Phosphothreonine

Modified residue

665

Phosphothreonine

Modified residue

1020

Phosphoserine

Modified residue

1402

Phosphothreonine; by autocatalysis By similarity

Modified residue

1414

Phosphothreonine; by autocatalysis By similarity

Natural variations

Natural variant

S → N

VAR_040680

Natural variant

443

C → S

VAR_040681

Experimental info

Sequence conflict

T → P in AAC97073. Ref.2

Sequence conflict

P → R in AAC97073. Ref.2

Sequence conflict

120

G → R in AAC97073. Ref.2

Sequence conflict

351

R → H in AAC97073. Ref.2

Sequence conflict

846

S → V in AAC97073. Ref.2

Sequence conflict

860

I → Y in AAC97073. Ref.2

Sequence conflict

879 – 880

DG → QR in AAC97073. Ref.2

Sequence conflict

935

S → R in AAC97073. Ref.2

Sequence conflict

1099

C → L in AAC97073. Ref.2

Sequence conflict

1106 – 1109

AVIP → CCYT in AAC97073. Ref.2

Sequence conflict

1202

D → V in AAC97073. Ref.2

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Sequences

Sequence

Length

Mass (Da)

Tools

Q13233-1 [UniParc].

Last modified June 12, 2007. Version 3.
Checksum: A5B436E94785243D
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FASTA

1,514

164,923

        10         20         30         40         50         60 
MAAAAGNRAS SSGFPGARAT SPEAGGGGGA LKASSAPAAA AGLLREAGSG GRERADWRRR 

        70         80         90        100        110        120 
QLRKVRSVEL DQLPEQPLFL AASPPASSTS PSPEPADAAG SGTGFQPVAV PPPHGAASRG 

       130        140        150        160        170        180 
GAHLTESVAA PDSGASSPAA AEPGEKRAPA AEPSPAAAPA GREMENKETL KGLHKMDDRP 

       190        200        210        220        230        240 
EERMIREKLK ATCMPAWKHE WLERRNRRGP VVVKPIPVKG DGSEMNHLAA ESPGEVQASA 

       250        260        270        280        290        300 
ASPASKGRRS PSPGNSPSGR TVKSESPGVR RKRVSPVPFQ SGRITPPRRA PSPDGFSPYS 

       310        320        330        340        350        360 
PEETNRRVNK VMRARLYLLQ QIGPNSFLIG GDSPDNKYRV FIGPQNCSCA RGTFCIHLLF 

       370        380        390        400        410        420 
VMLRVFQLEP SDPMLWRKTL KNFEVESLFQ KYHSRRSSRI KAPSRNTIQK FVSRMSNSHT 

       430        440        450        460        470        480 
LSSSSTSTSS SENSIKDEEE QMCPICLLGM LDEESLTVCE DGCRNKLHHH CMSIWAEECR 

       490        500        510        520        530        540 
RNREPLICPL CRSKWRSHDF YSHELSSPVD SPSSLRAAQQ QTVQQQPLAG SRRNQESNFN 

       550        560        570        580        590        600 
LTHYGTQQIP PAYKDLAEPW IQVFGMELVG CLFSRNWNVR EMALRRLSHD VSGALLLANG 

       610        620        630        640        650        660 
ESTGNSGGSS GSSPSGGATS GSSQTSISGD VVEACCSVLS MVCADPVYKV YVAALKTLRA 

       670        680        690        700        710        720 
MLVYTPCHSL AERIKLQRLL QPVVDTILVK CADANSRTSQ LSISTLLELC KGQAGELAVG 

       730        740        750        760        770        780 
REILKAGSIG IGGVDYVLNC ILGNQTESNN WQELLGRLCL IDRLLLEFPA EFYPHIVSTD 

       790        800        810        820        830        840 
VSQAEPVEIR YKKLLSLLTF ALQSIDNSHS MVGKLSRRIY LSSARMVTTV PHVFSKLLEM 

       850        860        870        880        890        900 
LSVSSSSTHF TRMRRRLMAI ADEVEIAEAI QLGVEDTLDG QQHNSFCRHL FPTTIWKPQR 

       910        920        930        940        950        960 
TVPLECTVHL EKTGKGLCAT KLSASSEDIS ERLASISVGP SSSTTTTTTT TEQPKPMVQT 

       970        980        990       1000       1010       1020 
KGRPHSQCLN SSPLSHHSQL MFPALSTPSS STPSVPAGTA TDVSKHRLQG FIPCRIPSAS 

      1030       1040       1050       1060       1070       1080 
PQTQRKFSLQ FHRNCPENKD SDKLSPVFTQ SRPLPSSNIH RPKPSRPTPG NTSKQGDPSK 

      1090       1100       1110       1120       1130       1140 
NSMTLDLNSS SKCDDSFGCS SNSSNAVIPS DETVFTPVEE KCRLDVNTEL NSSIEDLLEA 

      1150       1160       1170       1180       1190       1200 
SMPSSDTTVT FKSEVAVLSP EKAENDDTYK DDVNHNQKCK EKMEAEEEEA LAIAMAMSAS 

      1210       1220       1230       1240       1250       1260 
QDALPIVPQL QVENGEDIII IQQDTPETLP GHTKAKQPYR EDTEWLKGQQ IGLGAFSSCY 

      1270       1280       1290       1300       1310       1320 
QAQDVGTGTL MAVKQVTYVR NTSSEQEEVV EALREEIRMM SHLNHPNIIR MLGATCEKSN 

      1330       1340       1350       1360       1370       1380 
YNLFIEWMAG GSVAHLLSKY GAFKESVVIN YTEQLLRGLS YLHENQIIHR DVKGANLLID 

      1390       1400       1410       1420       1430       1440 
STGQRLRIAD FGAAARLASK GTGAGEFQGQ LLGTIAFMAP EVLRGQQYGR SCDVWSVGCA 

      1450       1460       1470       1480       1490       1500 
IIEMACAKPP WNAEKHSNHL ALIFKIASAT TAPSIPSHLS PGLRDVALRC LELQPQDRPP 

      1510 
SRELLKHPVF RTTW

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The DNA sequence and comparative analysis of human chromosome 5." Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. Rubin E.M. Nature 431:268-274(2004) [PubMed: 15372022] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[2]	"JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension." Xia Y., Wu Z., Su B., Murray B., Karin M. Genes Dev. 12:3369-3381(1998) [PubMed: 9808624] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 20-1514, FUNCTION, INTERACTION WITH MAP2K4.
[3]	"Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome 5." Vinik B.S., Kay E.S., Fiedorek F.T. Jr. Mamm. Genome 6:782-783(1995) [PubMed: 8597633] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1240-1276. Tissue: Leukocyte.
[4]	"The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms." Wong C.K., Luo W., Deng Y., Zou H., Ye Z., Lin S.-C. J. Biol. Chem. 279:39366-39373(2004) [PubMed: 15262978] [Abstract] Cited for: INTERACTION WITH AXIN1.
[5]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-657 AND THR-665, MASS SPECTROMETRY.
[6]	"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis." Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III J. Proteome Res. 7:1346-1351(2008) [PubMed: 18220336] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-292, MASS SPECTROMETRY.
[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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-292; SER-297; SER-300; SER-507; SER-511 AND SER-1020, MASS SPECTROMETRY.
[8]	"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. Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ASN-92 AND SER-443.
+	Additional computationally mapped references.

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Cross-references

Sequence databases
	AC008937 Genomic DNA. No translation available. AF042838 mRNA. Translation: AAC97073.1. U29671 Genomic DNA. Translation: AAB05828.1.
PIR	G01887.
RefSeq	NP_005912.1.
UniGene	Hs.657756
3D structure databases
HSSP	HSSP built from PDB template 1KV1 based on UniProtKB Q16539.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP:27520N.
IntAct	Q13233.
PTM databases
PhosphoSite	Q13233.
2-D gel databases
SWISS-2DPAGE	Q13233.
Genome annotation databases
Ensembl	ENSG00000095015. Homo sapiens. [Contig view]
GeneID	4214.
KEGG	hsa:4214.
Organism-specific databases
H-InvDB	HIX0024789.
HGNC	HGNC:6848. MAP3K1.
HPA	CAB004500.
MIM	600982. gene.
PharmGKB	PA30592.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOGENOM	Q13233.
HOVERGEN	Q13233.
Enzyme and pathway databases
Reactome	REACT_6900. Signaling in Immune System.
Gene expression databases
ArrayExpress	Q13233.
CleanEx	HS_MAP3K1.
GermOnline	ENSG00000095015. Homo sapiens.
Family and domain databases
InterPro	IPR015749. MAPKKK1. IPR000719. Prot_kinase_core. IPR017441. Protein_kinase_ATP_bd_CS. IPR017442. Se/Thr_pkinase-rel. IPR008271. Ser_thr_pkin_AS. IPR002290. Ser_thr_pkinase. IPR001841. Znf_RING. IPR013083. Znf_RING/FYVE/PHD. IPR007527. Znf_SWIM. [Graphical view]
Gene3D	G3DSA:3.30.40.10. Znf_RING/FYVE/PHD. 1 hit.
PANTHER	PTHR22986:SF65. MAPKKK1. 1 hit.
Pfam	PF00069. Pkinase. 1 hit. PF04434. SWIM. 1 hit. [Graphical view]
ProDom	PD000001. Prot_kinase. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00184. RING. 1 hit. SM00220. S_TKc. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. PS00518. ZF_RING_1. False negative. PS50089. ZF_RING_2. 1 hit. PS50966. ZF_SWIM. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	16613.
SOURCE	Search...

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Entry information

Entry name

M3K1_HUMAN

Accession

Primary (citable) accession number: Q13233

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	June 12, 2007
Last modified:	November 25, 2008
This is version 86 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Relevant documents

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

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

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

2-D gel databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents