AiPD: Autoinhibited Protein Database

Q9WTR2

Gene name	Map3k6 (Ask2, Mapkkk6, Mekk6)
Protein name	Mitogen-activated protein kinase kinase kinase 6
Names	EC 2.7.11.25 , Apoptosis signal-regulating kinase 2
Species	Mus musculus (Mouse)
KEGG Pathway
EC number	2.7.11.25: Protein-serine/threonine kinases
Protein Class

Descriptions

Apoptosis signal-regulating kinases (ASK1-3) are MAP3Ks that trigger cellular responses to redox stress and inflammatory cytokines and play vital roles in innate immunity and viral infection. When activated, ASK1?3 activates JNK and p38 via phosphorylation of MAP2Ks (MKK3/4/6/7). ASK1?3 shares a conserved architecture in which the central kinase domain is flanked on either side by additional domains, and multimeric association appears to be crucial to the activity of these domains. Regulatory factors, such as thioredoxin, associate with the N-terminal thioredoxin-binding domain to negatively regulate activity. Activity can be induced by oxidation, thioredoxin dissociation, or TRAF association (among other stimuli), at which point the activating pleckstrin homology surface becomes available for MAP2K association, activation loop priming, and phosphorylation.

Autoinhibitory domains (AIDs)

53-230 (Thioredoxin-binding domain) SS

Target domain	649-907 (Protein kinase domain)
Relief mechanism	Partner binding, Others
Assay

AID

53-230 (Thioredoxin-binding domain)

Target domain

649-907 (Protein kinase domain)

Relief mechanism

Partner binding (thioredoxin dissociation or TRAF association), Others (Oxidation)

Assay

Accessory elements

790-813 (Activation loop from InterPro)

Target domain	649-907 (Protein kinase domain)
Relief mechanism
Assay

References

Zhang R et al. (2004) "Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner", Circulation research, 94, 1483-91

Hatai T et al. (2000) "Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation", The Journal of biological chemistry, 275, 26576-81

Seong HA et al. (2011) "Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein", The Journal of biological chemistry, 286, 31123-35

Maruyama T et al. (2014) "Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses", Science signaling, 7, ra8

Weijman JF et al. (2017) "Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1", Proceedings of the National Academy of Sciences of the United States of America, 114, E2096-E2105

Autoinhibited structure

Activated structure

1 structures for Q9WTR2

Entry ID	Method	Resolution	Chain	Position	Source
AF-Q9WTR2-F1	Predicted				AlphaFoldDB

No variants for Q9WTR2

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
No variants for Q9WTR2

No associated diseases with Q9WTR2

7 regional properties for Q9WTR2

Type	Name	Position	InterPro Accession
domain	Protein kinase domain	649 - 907	IPR000719
active_site	Serine/threonine-protein kinase, active site	768 - 780	IPR008271
binding_site	Protein kinase, ATP binding site	655 - 678	IPR017441
domain	MAP3K, TRAFs-binding domain	130 - 508	IPR025136
domain	MAP3K, PH domain	524 - 620	IPR043969
domain	MAP3K, deoxyribohydrolase domain	75 - 115	IPR046872
domain	MAP3K, HisK-N-like globin domain	994 - 1119	IPR046873

Functions

		Description
EC Number	2.7.11.25	Protein-serine/threonine kinases
Subcellular Localization
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

No GO annotations of cellular component

Name	Definition
No GO annotations for cellular component

4 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
MAP kinase kinase kinase activity	Catalysis of the phosphorylation and activation of a MAP kinase kinase; each MAP kinase kinase can be phosphorylated by any of several MAP kinase kinase kinases.
metal ion binding	Binding to a metal ion.
protein serine kinase activity	Catalysis of the reactions

2 GO annotations of biological process

Name	Definition
cellular response to stress	Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating the organism is under stress. The stress is usually, but not necessarily, exogenous (e.g. temperature, humidity, ionizing radiation).
phosphorylation	The process of introducing a phosphate group into a molecule, usually with the formation of a phosphoric ester, a phosphoric anhydride or a phosphoric amide.

5 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
Q6ZN16	MAP3K15	Mitogen-activated protein kinase kinase kinase 15	Homo sapiens (Human)	SS
Q99683	MAP3K5	Mitogen-activated protein kinase kinase kinase 5	Homo sapiens (Human)	EV
O95382	MAP3K6	Mitogen-activated protein kinase kinase kinase 6	Homo sapiens (Human)	SS
A2AQW0	Map3k15	Mitogen-activated protein kinase kinase kinase 15	Mus musculus (Mouse)	PR
O35099	Map3k5	Mitogen-activated protein kinase kinase kinase 5	Mus musculus (Mouse)	SS

10	20	30	40	50	60
MAGPCPRAGV	LERAGSCWQD	PLAEALSRGR	SSPAVTGRGC	ARSRPLSVVY	VLTREPGPGV
70	80	90	100	110	120
EPGSGTEAEP	LPLRCLREAC	AQLQGTRPPP	QLRSLPFATL	ALGDTAALDS	FYNADVVVLE
130	140	150	160	170	180
VSSSLAQPSL	FYHLGVRESF	SMTNNVLLCS	QAELPDLQAL	REDVFQKNSD	CVGSYTLIPY
190	200	210	220	230	240
VVTATGRVLC	GDAGLLRGIA	DGLVQAGAGT	EALLTPLVGR	LVRLLEATPT	DSCGYFRETI
250	260	270	280	290	300
RQDIRQARER	FSGQQLRQEL	ARLQRRLDSV	ELLSPDIVMN	LLLSYRDVQD	YSAIIELVET
310	320	330	340	350	360
LQALPTCDVA	EQHNVCFHYT	FALNRRNRPG	DREKALAVLL	PLVKYEGPVA	PDLYCMCGRI
370	380	390	400	410	420
YKDMFFTSGF	QNAGHLEQAY	HWYRKAFDVE	PSLHSGINAA	VLLIAAGQHF	EDSEELRLIG
430	440	450	460	470	480
MKLACLLARK	GCVEKMQYYW	DVGFYLGAQI	LANDPIQVVL	AAEQLYKLNA	PIWYLVSVME
490	500	510	520	530	540
TFLLYQHFRP	TPEPSGGPPL	RAHFWLHFLL	QSCQPFKMAP	PQEDQCLVLV	LEINKVLLPA
550	560	570	580	590	600
RLEIQGTDPM	SAVTLSLLEP	ETQEDPSSWT	FPVTSICGIS	TSKLDQRCCF	LYALPPAQDV
610	620	630	640	650	660
QLCFPSVERC	QRFCGLIQVL	VMNPDSSAPT	EEAEGAREVL	EFDYEYSETG	ERLVLGRGTY
670	680	690	700	710	720
GVVYAGRDRH	TRVRIAIKEI	PERDSRFSQP	LHEEIALHKR	LRHKNIVRYL	GSASQGGYLK
730	740	750	760	770	780
IFMEEVPGGS	LSSLLRSVWG	PLKDNESTIS	FYTRQILQGL	SYLHENRIVH	RDIKGDNVLI
790	800	810	820	830	840
NTFSGLLKIS	DFGTSKRLAG	ITPCTETFTG	TLQYMAPEII	DQGPRGYGKA	ADIWSLGCTV
850	860	870	880	890	900
IEMATGRPPF	HELGSPQAAM	FQVGMYKVHP	PVPGSLSAEA	QAFLLRTFEP	DPRLRASAQE
910	920	930	940	950	960
LLGDPFLQPG	KRSRSPGSPR	HTPRPSGAPS	GPSSPSADSA	TQSQTFPRPQ	APSQHPPSPP
970	980	990	1000	1010	1020
KRCLSYGDTS	QLRVPEEPAA	EEPASPEESS	GLSLLHQESK	RRAMLAAVLE	QEVPTLAENL
1030	1040	1050	1060	1070	1080
LEQEQDSRLS	KIHVELLLRC	LGAQIHTPNR	RQLAQELRTL	QAQLRAQSLG	PALLKGPLFA
1090	1100	1110	1120	1130	1140
FPDAVKQILR	RRQIRPHWMF	VLDSLLSRAV	RAALAVLDAE	SEKKAVLPRS	EESSKEESQQ
1150	1160	1170	1180	1190	1200
KPQESQALQS	QLPPEQGPPS	LMVELGLLRA	ETDRLRDLLA	EKERECQALV	QQALHRVHAE
1210	1220	1230	1240	1250	1260
TRKYAPASET	PATLPKDQNL	VRWLQELSVD	PATIQTLLSH	SFTLQTLLTC	ATQDDLVYTR
1270	1280	1290
IRGGMVCRIW	RAILAQRAGA	TSVTPVPRDA	E