Reviewed, UniProtKB/Swiss-Prot Q99683 (M3K5_HUMAN)

Names and origin

Protein names

Recommended name:
    Mitogen-activated protein kinase kinase kinase 5
    EC=2.7.11.25
Alternative name(s):
    MAPK/ERK kinase kinase 5
      Short name(s)=MEK kinase 5, MEKK 5
    Apoptosis signal-regulating kinase 1
      Short name(s)=ASK-1

Gene names

Name:	MAP3K5
Synonyms:	ASK1, MAPKKK5, MEKK5

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	1374 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Component of a protein kinase signal transduction cascade. Phosphorylates and activates MAP2K4 and MAP2K6, which in turn activate the JNK and p38 MAP kinases, respectively. Overexpression induces apoptotic cell death.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Enzyme regulation	Contains an N-terminal autoinhibitory domain. Activated by phosphorylation at Thr-838, inhibited by phosphorylation at Ser-966 and Ser-1033. Binds to, and stabilizes MAP3K6 and is activated by MAP3K6 by phosphorylation on Thr-838.
Subunit structure	Homodimer when inactive. Binds both upstream activators and downstream substrates in multimolecular complexes. Associates with and inhibited by HIV-1 Nef. Interacts with DAB2IP.
Tissue specificity	Abundantly expressed in heart and pancreas.
Induction	By TNF-alpha. Inhibited by HIV-1 Nef.
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Host-virus interaction
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	activation of JNK activity Ref.2 Traceable author statement. Source: ProtInc induction of apoptosis by extracellular signals Ref.2 Traceable author statement. Source: ProtInc
Molecular function	ATP binding Ref.11 Inferred from direct assay. Source: UniProtKB MAP kinase kinase kinase activity Ref.2 Ref.11 Inferred from direct assay. Source: UniProtKB caspase activator activity Inferred from direct assay. Source: UniProtKB magnesium ion binding Ref.11 Inferred from direct assay. Source: UniProtKB protein homodimerization activity Ref.7 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		1	EBI-476263,EBI-476263
AKT1	P31749	2	EBI-476263,EBI-296087
DAXX	Q9UER7	4	EBI-476263,EBI-77321
FAS	P25445	1	EBI-476263,EBI-494743
Gstm2	P15626	1	EBI-476263,EBI-1209729	From a different organism.
GSTP1	P09211	1	EBI-476263,EBI-353467
Map3k6	Q9WTR2	1	EBI-476263,EBI-1254790	From a different organism.
Slk	O08815	1	EBI-476263,EBI-986112	From a different organism.
TRAF2	Q12933	1	EBI-476263,EBI-355744
YWHAZ	P63104	1	EBI-476263,EBI-347088

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 1374

1374

Mitogen-activated protein kinase kinase kinase 5

Regions

Domain

680 – 938

259

Protein kinase

Nucleotide binding

686 – 694

9

ATP By similarity

Sites

Active site

803

1

Proton acceptor By similarity

Binding site

709

1

ATP

Amino acid modifications

Modified residue

838

1

Phosphothreonine

Modified residue

958

1

Phosphoserine By similarity

Modified residue

966

1

Phosphoserine

Modified residue

1029

1

Phosphoserine

Modified residue

1033

1

Phosphoserine

Natural variations

Natural variant

1006

1

G → R

Natural variant

1214

1

I → T

Natural variant

1250

1

I → V

Natural variant

1314

1

T → I

Natural variant

1315

1

D → N

Experimental info

Mutagenesis

709

1

K → M: Loss of kinase activity. Inhibits activation of JNK and apoptosis mediated by TNFRSF6 and DAXX

Mutagenesis

709

1

K → R: Loss of kinase activity. Abolishes DAXX-mediated apoptosis

Mutagenesis

966

1

S → A: Enhanced induction of apoptosis, increased kinase activity, and loss of YWHAG binding

Mutagenesis

1033

1

S → A: Enhanced induction of apoptosis and increased kinase activity

Secondary structure

1

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1374

Helix Strand Turn

Details...

Beta strand

671 – 714

44

Helix

720 – 730

11

Beta strand

731 – 761

31

Helix

762 – 767

6

Beta strand

768 – 770

3

Beta strand

773 – 776

4

Helix

777 – 796

20

Beta strand

797 – 830

34

Beta strand

838 – 846

9

Helix

848 – 853

6

Beta strand

855 – 861

7

Helix

862 – 876

15

Beta strand

880 – 888

9

Helix

889 – 897

9

Beta strand

898 – 900

3

Beta strand

905 – 908

4

Helix

909 – 916

8

Beta strand

917 – 928

12

Helix

929 – 933

5

Beta strand

934 – 940

7

Sequences

	Sequence		Length	Mass (Da)
	Q99683-1 [UniParc]. Last modified May 1, 1997. Version 1. Checksum: 265BDC65968AF985	FASTA	1,374	154,537
	10 20 30 40 50 60 MSTEADEGIT FSVPPFAPSG FCTIPEGGIC RRGGAAAVGE GEEHQLPPPP PGSFWNVESA 70 80 90 100 110 120 AAPGIGCPAA TSSSSATRGR GSSVGGGSRR TTVAYVINEA SQGQLVVAES EALQSLREAC 130 140 150 160 170 180 ETVGATLETL HFGKLDFGET TVLDRFYNAD IAVVEMSDAF RQPSLFYHLG VRESFSMANN 190 200 210 220 230 240 IILYCDTNSD SLQSLKEIIC QKNTMCTGNY TFVPYMITPH NKVYCCDSSF MKGLTELMQP 250 260 270 280 290 300 NFELLLGPIC LPLVDRFIQL LKVAQASSSQ YFRESILNDI RKARNLYTGK ELAAELARIR 310 320 330 340 350 360 QRVDNIEVLT ADIVINLLLS YRDIQDYDSI VKLVETLEKL PTFDLASHHH VKFHYAFALN 370 380 390 400 410 420 RRNLPGDRAK ALDIMIPMVQ SEGQVASDMY CLVGRIYKDM FLDSNFTDTE SRDHGASWFK 430 440 450 460 470 480 KAFESEPTLQ SGINYAVLLL AAGHQFESSF ELRKVGVKLS SLLGKKGNLE KLQSYWEVGF 490 500 510 520 530 540 FLGASVLAND HMRVIQASEK LFKLKTPAWY LKSIVETILI YKHFVKLTTE QPVAKQELVD 550 560 570 580 590 600 FWMDFLVEAT KTDVTVVRFP VLILEPTKIY QPSYLSINNE VEEKTISIWH VLPDDKKGIH 610 620 630 640 650 660 EWNFSASSVR GVSISKFEER CCFLYVLHNS DDFQIYFCTE LHCKKFFEMV NTITEEKGRS 670 680 690 700 710 720 TEEGDCESDL LEYDYEYDEN GDRVVLGKGT YGIVYAGRDL SNQVRIAIKE IPERDSRYSQ 730 740 750 760 770 780 PLHEEIALHK HLKHKNIVQY LGSFSENGFI KIFMEQVPGG SLSALLRSKW GPLKDNEQTI 790 800 810 820 830 840 GFYTKQILEG LKYLHDNQIV HRDIKGDNVL INTYSGVLKI SDFGTSKRLA GINPCTETFT 850 860 870 880 890 900 GTLQYMAPEI IDKGPRGYGK AADIWSLGCT IIEMATGKPP FYELGEPQAA MFKVGMFKVH 910 920 930 940 950 960 PEIPESMSAE AKAFILKCFE PDPDKRACAN DLLVDEFLKV SSKKKKTQPK LSALSAGSNE 970 980 990 1000 1010 1020 YLRSISLPVP VLVEDTSSSS EYGSVSPDTE LKVDPFSFKT RAKSCGERDV KGIRTLFLGI 1030 1040 1050 1060 1070 1080 PDENFEDHSA PPSPEEKDSG FFMLRKDSER RATLHRILTE DQDKIVRNLM ESLAQGAEEP 1090 1100 1110 1120 1130 1140 KLKWEHITTL IASLREFVRS TDRKIIATTL SKLKLELDFD SHGISQVQVV LFGFQDAVNK 1150 1160 1170 1180 1190 1200 VLRNHNIKPH WMFALDSIIR KAVQTAITIL VPELRPHFSL ASESDTADQE DLDVEDDHEE 1210 1220 1230 1240 1250 1260 QPSNQTVRRP QAVIEDAVAT SGVSTLSSTV SHDSQSAHRS LNVQLGRMKI ETNRLLEELV 1270 1280 1290 1300 1310 1320 RKEKELQALL HRAIEEKDQE IKHLKLKSQP IEIPELPVFH LNSSGTNTED SELTDWLRVN 1330 1340 1350 1360 1370 GADEDTISRF LAEDYTLLDV LYYVTRDDLK CLRLRGGMLC TLWKAIIDFR NKQT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase." Wang X.S., Diener K., Jannuzzi D., Trollinger D., Tan T.-H., Lichenstein H., Zukowski M., Yao Z. J. Biol. Chem. 271:31607-31611(1996) [PubMed: 8940179] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]	"Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways." Ichijo H., Nishida E., Irie K., ten Dijke P., Saitoh M., Moriguchi T., Takagi M., Matsumoto K., Miyazono K., Gotoh Y. Science 275:90-94(1997) [PubMed: 8974401] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[3]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Eye and Lung.
[5]	"Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx." Chang H.Y., Nishitoh H., Yang X., Ichijo H., Baltimore D. Science 281:1860-1863(1998) [PubMed: 9743501] [Abstract] Cited for: INTERACTION WITH DAXX, MUTAGENESIS OF LYS-709.
[6]	"HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell." Geleziunas R., Xu W., Takeda K., Ichijo H., Greene W.C. Nature 410:834-838(2001) [PubMed: 11298454] [Abstract] Cited for: INTERACTION WITH HIV-1 NEF, INHIBITION BY HIV-1 NEF.
[7]	"Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer." Tobiume K., Saitoh M., Ichijo H. J. Cell. Physiol. 191:95-104(2002) [PubMed: 11920685] [Abstract] Cited for: FUNCTION, HOMODIMERIZATION, ENZYME REGULATION, PHOSPHORYLATION AT THR-838.
[8]	"AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3." Zhang R., He X., Liu W., Lu M., Hsieh J.-T., Min W. J. Clin. Invest. 111:1933-1943(2003) [PubMed: 12813029] [Abstract] Cited for: INTERACTION WITH DAB2IP.
[9]	"AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-induced ASK1-JNK activation." Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W. J. Biol. Chem. 279:44955-44965(2004) [PubMed: 15310755] [Abstract] Cited for: INTERACTION WITH DAB2IP.
[10]	"Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034." Fujii K., Goldman E.H., Park H.R., Zhang L., Chen J., Fu H. Oncogene 23:5099-5104(2004) [PubMed: 15094778] [Abstract] Cited for: ENZYME REGULATION, PHOSPHORYLATION AT SER-966 AND SER-1033, MUTAGENESIS OF SER-966 AND SER-1033, INTERACTION WITH YWHAG.
[11]	"Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1." Takeda K., Shimozono R., Noguchi T., Umeda T., Morimoto Y., Naguro I., Tobiume K., Saitoh M., Matsuzawa A., Ichijo H. J. Biol. Chem. 282:7522-7531(2007) [PubMed: 17210579] [Abstract] Cited for: ENZYME REGULATION, INTERACTION WITH MAP3K5, PHOSPHORYLATION AT THR-838, MUTAGENESIS OF LYS-709.
[12]	"Phosphoproteome of resting human platelets." Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A. J. Proteome Res. 7:526-534(2008) [PubMed: 18088087] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1029 AND SER-1033, MASS SPECTROMETRY. Tissue: Platelet.
[13]	"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] ARG-1006; THR-1214; VAL-1250; ILE-1314 AND ASN-1315.

Cross-references

Sequence databases

EMBLGenBankDDBJ

U67156 mRNA. Translation: AAC50894.1.
D84476 mRNA. Translation: BAA12684.2.
AL024508, AL121933 Genomic DNA. Translation: CAI20176.1.
AL121933, AL024508 Genomic DNA. Translation: CAI15470.1.
BC054503 mRNA. Translation: AAH54503.1.
BC088829 mRNA. Translation: AAH88829.1.

RefSeq

NP_005914.1.

UniGene

Hs.186486

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2CLQ	X-ray	2.30	A/B	659-951	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q99683.

PTM databases

PhosphoSite

Q99683.

Genome annotation databa