AiPD: Autoinhibited Protein Database

P52564

Gene name	MAP2K6 (MEK6, MKK6, PRKMK6, SKK3)
Protein name	Dual specificity mitogen-activated protein kinase kinase 6
Names	MAP kinase kinase 6, MAPKK 6, MAPK/ERK kinase 6, MEK 6, Stress-activated protein kinase kinase 3, SAPK kinase 3, SAPKK-3, SAPKK3
Species	Homo sapiens (Human)
KEGG Pathway	hsa:5608
EC number	2.7.12.2: Dual-specificity kinases (those acting on Ser/Thr and Tyr residues)
Protein Class	DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 5-RELATED (PTHR48013)

Descriptions

MAP2K6 is Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. The mechanism of autoinhibition of MAP2K6 differents from those observed for MAP2K1/4 regulation. The activation loop consisting of 3 short α-helices (AH1, AH2, AH3), which are significant in forming the autoinhibition state. AH1, AH2 and AH3 stabilizes the MAP2K6 in the inactive conformation by several interactions between themselves and main body of kinase domain. The phospho-AH2 presumably releases the molecular break and triggers a conformational transitions to the flexible states.

Autoinhibitory domains (AIDs)

Accessory elements

196-218 (Activation loop from InterPro)

Target domain	53-314 (Protein kinase domain)
Relief mechanism	PTM
Assay	Structural analysis

References

Matsumoto T et al. (2012) "Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state", Journal of biochemistry, 151, 541-9

Autoinhibited structure

Activated structure

9 structures for P52564

Entry ID	Method	Resolution	Chain	Position	Source
2Y8O	X-ray	195 A	B	4-17	PDB
3ENM	X-ray	235 A	A/B/C/D	45-332	PDB
3FME	X-ray	226 A	A	47-334	PDB
3VN9	X-ray	260 A	A	1-334	PDB
5ETF	X-ray	240 A	B	4-17	PDB
8A8M	EM	400 A	B	15-334	PDB
8P7J	X-ray	240 A	A/B	47-334	PDB
8PM3	X-ray	200 A	A/B/C/D	47-334	PDB
AF-P52564-F1	Predicted				AlphaFoldDB

125 variants for P52564

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
rs1274652122 CA400847917	9	R>*		No	ClinGen gnomAD
CA400847965 rs1403041894	12	G>R		No	ClinGen gnomAD
CA293628198 rs867782808	13	L>F		No	ClinGen Ensembl
CA293628199 rs1024972303	26	S>G		No	ClinGen TOPMed gnomAD
rs529602401 CA8738080	28	T>A		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
rs201975195 CA8738081	28	T>I		No	ClinGen ESP ExAC TOPMed gnomAD
rs201975195 CA8738083	28	T>K		No	ClinGen ESP ExAC TOPMed gnomAD
CA8738082 rs201975195	28	T>R		No	ClinGen ESP ExAC TOPMed gnomAD
rs1339631432 CA400849857	32	D>N		No	ClinGen TOPMed
CA400849869 rs1369882333	33	L>I		No	ClinGen gnomAD
CA8738106 rs749911524	38	C>F		No	ClinGen ExAC gnomAD
rs1455327405 CA400849959	41	I>T		No	ClinGen TOPMed
rs755874435 CA8738131	48	V>M		No	ClinGen ExAC gnomAD
CA400850172 rs1278027812	54	E>G		No	ClinGen TOPMed
CA8738132 rs200064105	56	I>L		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
CA400850199 rs1328494114	56	I>M		No	ClinGen TOPMed
rs1195483404 CA400850196	56	I>T		No	ClinGen gnomAD
CA400850192 rs200064105	56	I>V		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
rs753824437 CA8738133 COSM194228	61	R>*	large_intestine [Cosmic]	No	ClinGen cosmic curated ExAC gnomAD
CA400850274 rs1158673417	63	A>V		No	ClinGen gnomAD
CA400850306 rs1340856740	66	V>L		No	ClinGen TOPMed gnomAD
CA8738138 rs781294587	67	V>L		No	ClinGen ExAC gnomAD
rs748491002 CA8738139	69	K>N		No	ClinGen ExAC gnomAD
rs1346123064 CA400850346	69	K>R		No	ClinGen Ensembl
CA400850359 rs1176497057	70	M>T		No	ClinGen TOPMed
rs559452659 CA293629397	71	R>L		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
rs559452659 CA8738141	71	R>Q		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
CA8738140 rs770061826	71	R>W		No	ClinGen ExAC TOPMed gnomAD
CA8738143 rs749769191	73	V>L		No	ClinGen ExAC gnomAD
CA8738142 rs749769191	73	V>M		No	ClinGen ExAC gnomAD
rs371754193 CA8738146	76	G>R		No	ClinGen ESP ExAC TOPMed gnomAD
rs1335646150 CA400850432	76	G>V		No	ClinGen gnomAD
CA8738147 rs775010197	78	I>V		No	ClinGen ExAC gnomAD
CA8738148 rs760441802	81	V>A		No	ClinGen ExAC TOPMed gnomAD
CA400851127 rs1426115901	83	R>Q		No	ClinGen gnomAD
CA400851123 rs761726135	83	R>W		No	ClinGen ExAC TOPMed gnomAD
CA400851139 rs1598305571	84	I>T		No	ClinGen Ensembl
rs750395227 CA8738172	85	R>*		No	ClinGen ExAC gnomAD
rs777989992 CA8738177	90	S>N		No	ClinGen ExAC gnomAD
rs1280475521 CA400851300	95	R>Q		No	ClinGen gnomAD
rs144625593 CA8738178	95	R>W		No	ClinGen ESP ExAC TOPMed gnomAD
CA400851316 rs1486366643	97	L>M		No	ClinGen gnomAD
CA8738179 rs757620929	98	M>T		No	ClinGen ExAC gnomAD
rs1598305608 CA400851351	99	D>G		No	ClinGen Ensembl
CA400851422 rs1598305622	107	V>G		No	ClinGen Ensembl
CA400851462 rs1362730786	110	P>S		No	ClinGen Ensembl
rs746347515 CA8738181	112	T>I		No	ClinGen ExAC gnomAD
CA400851574 rs1168475716	118	A>T		No	ClinGen gnomAD
CA8738183 rs779399972	121	R>W		No	ClinGen ExAC gnomAD
rs758300138 CA293629682	125	V>M		No	ClinGen Ensembl
rs747793006 CA8738206	127	I>V		No	ClinGen ExAC gnomAD
CA400852108 rs1254094815	132	M>T		No	ClinGen TOPMed
rs961760860 CA293629683	136	L>P		No	ClinGen Ensembl
rs895326787 CA293629684	138	K>E		No	ClinGen TOPMed
rs1254677215 CA400852287	142	Q>L		No	ClinGen gnomAD
CA8738208 rs373776681	144	I>V		No	ClinGen ESP ExAC TOPMed gnomAD
rs749127643 CA8738209	146	K>E		No	ClinGen ExAC gnomAD
rs770713723 CA8738210	148	Q>H		No	ClinGen ExAC gnomAD
rs759535579 CA8738212	153	D>G		No	ClinGen ExAC gnomAD
CA8738213 rs764145262	156	G>R		No	ClinGen ExAC TOPMed gnomAD
rs1392640042 CA400852511	157	K>E		No	ClinGen gnomAD
CA400852522 rs761992405	157	K>N		No	ClinGen ExAC gnomAD
CA400852526 rs1349519186	158	I>L		No	ClinGen gnomAD
rs765475487 CA8738216	159	A>S		No	ClinGen ExAC TOPMed gnomAD
rs765475487 CA400852536	159	A>T		No	ClinGen ExAC TOPMed gnomAD
CA400852548 rs1294330667	160	V>I		No	ClinGen gnomAD
CA8738233 rs761904827	162	I>L		No	ClinGen ExAC TOPMed gnomAD
CA400852647 rs761904827	162	I>V		No	ClinGen ExAC TOPMed gnomAD
rs765320378 CA8738234	170	H>R		No	ClinGen ExAC gnomAD
CA400852769 rs1231234654	172	K>E		No	ClinGen gnomAD
rs776064610 CA293629751	178	R>S		No	ClinGen Ensembl
rs1192075206 CA400853044	182	P>S		No	ClinGen TOPMed
rs1159376383 CA400853080	185	V>A		No	ClinGen gnomAD
rs1413597818 CA400853073	185	V>I		No	ClinGen gnomAD
CA8738252 rs769915246	186	L>V		No	ClinGen ExAC TOPMed gnomAD
CA400853091 rs1459170248	187	I>L		No	ClinGen gnomAD
rs773226307 CA8738253	188	N>S		No	ClinGen ExAC gnomAD
CA8738254 rs763219277	190	L>I		No	ClinGen ExAC TOPMed gnomAD
CA293630040 rs891541948	191	G>S		No	ClinGen TOPMed gnomAD
CA400853262 rs1598309461	205	V>G		No	ClinGen Ensembl
CA400853267 rs1598309469	206	D>G		No	ClinGen Ensembl
CA400853277 rs1331402145	208	V>F		No	ClinGen gnomAD
rs146813017 CA8738258	212	I>V		No	ClinGen ESP ExAC TOPMed gnomAD
rs1267201205 CA400853338	214	A>T		No	ClinGen gnomAD
rs1308762828 CA400854018	228	E>G		No	ClinGen gnomAD
CA293630157 rs201074921	230	N>S		No	ClinGen 1000Genomes gnomAD
rs1219744904 CA400854061	232	K>E		No	ClinGen TOPMed
CA8738283 rs750062020	237	K>N		No	ClinGen ExAC gnomAD
CA293630342 rs958990701	248	I>T		No	ClinGen TOPMed
CA293630343 rs972763606	251	A>T		No	ClinGen Ensembl
rs1218813240 CA400854406	252	I>V		No	ClinGen TOPMed gnomAD
CA8738299 rs146595343	254	R>Q		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
CA400854452 rs1332003828	257	Y>H		No	ClinGen gnomAD
rs1240194085 CA400854478	259	S>P		No	ClinGen TOPMed
rs74734606 CA293630346	273	E>D		No	ClinGen Ensembl
rs772746071 CA8738302	274	P>S		No	ClinGen ExAC gnomAD
rs868233930 CA293630347	276	P>L		No	ClinGen Ensembl
rs371824152 CA293630349	279	P>S		No	ClinGen ESP
CA8738304 rs766038170	280	A>V		No	ClinGen ExAC TOPMed gnomAD
rs1303243625 CA400854747	281	D>E		No	ClinGen TOPMed
rs1198336138 CA400854761	282	K>R		No	ClinGen gnomAD
CA293630350 rs981405021	284	S>T		No	ClinGen TOPMed gnomAD
CA8738306 rs754746951	285	A>S		No	ClinGen ExAC gnomAD
rs1250454716 CA400854843	287	F>V		No	ClinGen TOPMed gnomAD
CA8738308 rs752575343	289	D>G		No	ClinGen ExAC gnomAD
CA8738309 rs756162581	291	T>I		No	ClinGen ExAC gnomAD
rs779115980 CA8738310	292	S>A		No	ClinGen ExAC gnomAD
CA400854933 rs1467832694	292	S>L		No	ClinGen gnomAD
rs780237320 CA8738334	295	L>*		No	ClinGen ExAC gnomAD
CA8738335 rs751724484	298	N>D		No	ClinGen ExAC gnomAD
CA8738337 rs781386309	300	K>R		No	ClinGen ExAC TOPMed gnomAD
rs770241284 CA8738339	304	T>I		No	ClinGen ExAC gnomAD
rs1165141750 CA400856478	305	Y>F		No	ClinGen gnomAD
rs1000985630 CA293631391	306	P>L		No	ClinGen TOPMed gnomAD
CA400856938 rs1394858277	314	F>S		No	ClinGen gnomAD
CA293631941 rs554043409	314	F>V		No	ClinGen gnomAD
rs1262075093 CA400856968	317	H>R		No	ClinGen TOPMed
CA293631942 rs149844958	317	H>Y		No	ClinGen ESP TOPMed
CA400857012 rs1307184813	321	G>R		No	ClinGen gnomAD
rs202101413 CA8738363	326	S>F		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
rs775295505 CA8738364	328	V>L		No	ClinGen ExAC gnomAD
CA293631944 rs879401388	329	K>R		No	ClinGen TOPMed
CA8738365 rs746716355	330	L>R		No	ClinGen ExAC TOPMed gnomAD
rs1406308257 CA400857129	330	L>V		No	ClinGen TOPMed
CA8738366 rs768566132	333	G>V		No	ClinGen ExAC TOPMed gnomAD

No associated diseases with P52564

3 regional properties for P52564

Type	Name	Position	InterPro Accession
domain	Protein kinase domain	53 - 314	IPR000719
active_site	Serine/threonine-protein kinase, active site	175 - 187	IPR008271
binding_site	Protein kinase, ATP binding site	59 - 82	IPR017441

Functions

		Description
EC Number	2.7.12.2	Dual-specificity kinases (those acting on Ser/Thr and Tyr residues)
Subcellular Localization	Nucleus Cytoplasm Cytoplasm, cytoskeleton	Binds to microtubules
PANTHER Family	PTHR48013	DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 5-RELATED
PANTHER Subfamily	PTHR48013:SF12	DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 6
PANTHER Protein Class	non-receptor serine/threonine protein kinase protein modifying enzyme
PANTHER Pathway Category	p38 MAPK pathway MKK6 Oxidative stress response MKK3/6 Gonadotropin-releasing hormone receptor pathway MKK3/6 FGF signaling pathway MKK3,6 EGF receptor signaling pathway MKK3,6 Ras Pathway MKK3/6 CCKR signaling map MAP2K6

3 GO annotations of cellular component

Name	Definition
cytoskeleton	A cellular structure that forms the internal framework of eukaryotic and prokaryotic cells. The cytoskeleton includes intermediate filaments, microfilaments, microtubules, the microtrabecular lattice, and other structures characterized by a polymeric filamentous nature and long-range order within the cell. The various elements of the cytoskeleton not only serve in the maintenance of cellular shape but also have roles in other cellular functions, including cellular movement, cell division, endocytosis, and movement of organelles.
cytosol	The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
nucleoplasm	That part of the nuclear content other than the chromosomes or the nucleolus.

9 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
identical protein binding	Binding to an identical protein or proteins.
MAP kinase kinase activity	Catalysis of the concomitant phosphorylation of threonine (T) and tyrosine (Y) residues in a Thr-Glu-Tyr (TEY) thiolester sequence in a MAP kinase (MAPK) substrate.
phosphatase activator activity	Binds to and increases the activity of a phosphatase, an enzyme which catalyzes of the removal of a phosphate group from a substrate molecule.
protein kinase binding	Binding to a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate.
protein serine kinase activity	Catalysis of the reactions: ATP + protein serine = ADP + protein serine phosphate.
protein serine/threonine kinase activator activity	Binds to and increases the activity of a protein serine/threonine kinase.
protein serine/threonine kinase activity	Catalysis of the reactions: ATP + protein serine = ADP + protein serine phosphate, and ATP + protein threonine = ADP + protein threonine phosphate.
protein tyrosine kinase activity	Catalysis of the reaction: ATP + a protein tyrosine = ADP + protein tyrosine phosphate.

21 GO annotations of biological process

Name	Definition
apoptotic process	A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathway phase) which trigger an execution phase. The execution phase is the last step of an apoptotic process, and is typically characterized by rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. When the execution phase is completed, the cell has died.
bone development	The process whose specific outcome is the progression of bone over time, from its formation to the mature structure. Bone is the hard skeletal connective tissue consisting of both mineral and cellular components.
cardiac muscle contraction	Muscle contraction of cardiac muscle tissue.
cellular response to sorbitol	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 sorbitol stimulus.
cellular senescence	A cell aging process stimulated in response to cellular stress, whereby normal cells lose the ability to divide through irreversible cell cycle arrest.
DNA damage induced protein phosphorylation	The widespread phosphorylation of various molecules, triggering many downstream processes, that occurs in response to the detection of DNA damage.
MAPK cascade	An intracellular protein kinase cascade containing at least a MAPK, a MAPKK and a MAP3K. The cascade can also contain an additional tiers: the upstream MAP4K. The kinases in each tier phosphorylate and activate the kinase in the downstream tier to transmit a signal within a cell.
negative regulation of cold-induced thermogenesis	Any process that stops, prevents, or reduces the rate of cold-induced thermogenesis.
nucleotide-binding oligomerization domain containing signaling pathway	The series of molecular signals initiated by the binding of a ligand (such as a bacterial peptidoglycan) to a cytoplasmic nucleotide-binding oligomerization domain containing (NOD) protein receptor, and ending with regulation of a downstream cellular process.
osteoblast differentiation	The process whereby a relatively unspecialized cell acquires the specialized features of an osteoblast, a mesodermal or neural crest cell that gives rise to bone.
ovulation cycle process	A process involved in the sexual cycle seen in females, often with physiologic changes in the endometrium that recur at regular intervals during the reproductive years.
positive regulation of apoptotic process	Any process that activates or increases the frequency, rate or extent of cell death by apoptotic process.
positive regulation of MAP kinase activity	Any process that activates or increases the frequency, rate or extent of MAP kinase activity.
positive regulation of nitric-oxide synthase biosynthetic process	Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of a nitric oxide synthase enzyme.
positive regulation of prostaglandin secretion	Any process that activates or increases the frequency, rate or extent of the regulated release of a prostaglandin from a cell.
regulation of cell cycle	Any process that modulates the rate or extent of progression through the cell cycle.
regulation of signal transduction by p53 class mediator	Any process that modulates the frequency, rate or extent of signal transduction by p53 class mediator.
response to ischemia	Any process that results in a change in state or activity of an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a inadequate blood supply.
response to xenobiotic stimulus	Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus from a xenobiotic, a compound foreign to the organim exposed to it. It may be synthesized by another organism (like ampicilin) or it can be a synthetic chemical.
signal transduction	The cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell. Signal transduction begins with reception of a signal (e.g. a ligand binding to a receptor or receptor activation by a stimulus such as light), or for signal transduction in the absence of ligand, signal-withdrawal or the activity of a constitutively active receptor. Signal transduction ends with regulation of a downstream cellular process, e.g. regulation of transcription or regulation of a metabolic process. Signal transduction covers signaling from receptors located on the surface of the cell and signaling via molecules located within the cell. For signaling between cells, signal transduction is restricted to events at and within the receiving cell.
stress-activated MAPK cascade	The series of molecular signals in which a stress-activated MAP kinase cascade relays a signal; MAP kinase cascades involve at least three protein kinase activities and culminate in the phosphorylation and activation of a MAP kinase.

11 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
Q5E9X2	MAP2K6	Dual specificity mitogen-activated protein kinase kinase 6	Bos taurus (Bovine)	EV
O14733	MAP2K7	Dual specificity mitogen-activated protein kinase kinase 7	Homo sapiens (Human)	PR
P46734	MAP2K3	Dual specificity mitogen-activated protein kinase kinase 3	Homo sapiens (Human)	SS
P45985	MAP2K4	Dual specificity mitogen-activated protein kinase kinase 4	Homo sapiens (Human)	EV
Q13163	MAP2K5	Dual specificity mitogen-activated protein kinase kinase 5	Homo sapiens (Human)	PR
P36507	MAP2K2	Dual specificity mitogen-activated protein kinase kinase 2	Homo sapiens (Human)	EV
Q02750	MAP2K1	Dual specificity mitogen-activated protein kinase kinase 1	Homo sapiens (Human)	EV
O09110	Map2k3	Dual specificity mitogen-activated protein kinase kinase 3	Mus musculus (Mouse)	PR
P70236	Map2k6	Dual specificity mitogen-activated protein kinase kinase 6	Mus musculus (Mouse)	EV
G5EDF7	sek-1	Dual specificity mitogen-activated protein kinase kinase sek-1	Caenorhabditis elegans	PR
Q9DGE0	map2k6	Dual specificity mitogen-activated protein kinase kinase 6	Danio rerio (Zebrafish) (Brachydanio rerio)	PR

10	20	30	40	50	60
MSQSKGKKRN	PGLKIPKEAF	EQPQTSSTPP	RDLDSKACIS	IGNQNFEVKA	DDLEPIMELG
70	80	90	100	110	120
RGAYGVVEKM	RHVPSGQIMA	VKRIRATVNS	QEQKRLLMDL	DISMRTVDCP	FTVTFYGALF
130	140	150	160	170	180
REGDVWICME	LMDTSLDKFY	KQVIDKGQTI	PEDILGKIAV	SIVKALEHLH	SKLSVIHRDV
190	200	210	220	230	240
KPSNVLINAL	GQVKMCDFGI	SGYLVDSVAK	TIDAGCKPYM	APERINPELN	QKGYSVKSDI
250	260	270	280	290	300
WSLGITMIEL	AILRFPYDSW	GTPFQQLKQV	VEEPSPQLPA	DKFSAEFVDF	TSQCLKKNSK
310	320	330
ERPTYPELMQ	HPFFTLHESK	GTDVASFVKL	ILGD