AiPD: Autoinhibited Protein Database

Q03526

Gene name	Itk (Emt, Tlk, Tsk)
Protein name	Tyrosine-protein kinase ITK/TSK
Names	EC 2.7.10.2 , IL-2-inducible T-cell kinase , Kinase EMT , Kinase TLK , T-cell-specific kinase
Species	Mus musculus (Mouse)
KEGG Pathway	mmu:16428
EC number	2.7.10.2: Protein-tyrosine kinases
Protein Class

Descriptions

Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase belonging to the TEC family, and is expressed primarily in B cells and myeloid cells, where it functions downstream of receptors including the B-cell receptor, Fc receptors, and toll-like receptors. BTK is autoinhibited by its SH3 and SH2 domains, forming a compact autoinhibitory conformation on the distal surface of the kinase domain. Additionally, there exists another autoinhibitory interface on the activation loop face of the kinase domain, which is occupied by the Pleckstrin homology and Tec homology (PHTH) domain. B-cell receptor engagement lead to BTK activation (via phosphorylation on Y551 in the activation loop), which results in the direct phosphorylation and activation of phospholipase C gamma 2 triggering calcium flux and subsequent regulation of gene transcription.

Autoinhibitory domains (AIDs)

177-344 (SH3 and SH2 domain) SS

Target domain	363-618 (Protein kinase domain)
Relief mechanism	PTM
Assay

AID

177-344 (SH3 and SH2 domain)

Target domain

363-618 (Protein kinase domain)

Relief mechanism

PTM (Phosphorylation at Tyr551)

Assay

5-153 (Pleckstrin homology and Tec homology domain) SS

Target domain	363-618 (Protein kinase domain)
Relief mechanism	PTM
Assay

AID

5-153 (Pleckstrin homology and Tec homology domain)

Target domain

363-618 (Protein kinase domain)

Relief mechanism

PTM (Phosphorylation at Tyr551)

Assay

Accessory elements

504-528 (Activation loop from InterPro)

Target domain	363-620 (Protein kinase domain)
Relief mechanism
Assay

References

Joseph RE et al. (2020) "Differential impact of BTK active site inhibitors on the conformational state of full-length BTK", eLife, 9,

Kueffer LE et al. (2021) "Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK", Frontiers in cell and developmental biology, 9, 655489

Joseph RE et al. (2017) "Achieving a Graded Immune Response: BTK Adopts a Range of Active/Inactive Conformations Dictated by Multiple Interdomain Contacts", Structure (London, England : 1993), 25, 1481-1494.e4

Wang Q et al. (2015) "Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate", eLife, 4,

Nocka LM et al. (2023) "Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2", eLife, 12,

Lowe J et al. (2022) "Conformational switches that control the TEC kinase - PLCγ signaling axis", Journal of structural biology: X, 6, 100061

Boyken SE et al. (2014) "A conserved isoleucine maintains the inactive state of Bruton's tyrosine kinase", Journal of molecular biology, 426, 3656-69

Autoinhibited structure

Activated structure

13 structures for Q03526

Entry ID	Method	Resolution	Chain	Position	Source
1AWJ	NMR	-	A	160-236	PDB
1LUI	NMR	-	A	238-344	PDB
1LUK	NMR	-	A	238-344	PDB
1LUM	NMR	-	A	238-344	PDB
1LUN	NMR	-	A	238-344	PDB
2ETZ	NMR	-	A	238-344	PDB
2EU0	NMR	-	A	238-344	PDB
2K79	NMR	-			PDB
2K7A	NMR	-			PDB
2RN8	NMR	-	A	177-238	PDB
2RNA	NMR	-	A	177-238	PDB
3S9K	X-ray	235 A	A	236-344	PDB
AF-Q03526-F1	Predicted				AlphaFoldDB

29 variants for Q03526

Variant ID(s)	Position	Change	Diseaes Association	Provenance
rs3389157142	41	F>V	No	EVA
rs3389161795	80	F>L	No	EVA
rs3548575431	89	V>M	No	EVA
rs3389152425	118	N>T	No	EVA
rs3389122656	122	L>P	No	EVA
rs3389154800	166	T>I	No	EVA
rs3389157169	177	P>A	No	EVA
rs3389090470	198	L>V	No	EVA
rs3389161837	220	K>N	No	EVA
rs215374086	251	S>N	No	EVA
rs3389154795	273	S>Y	No	EVA
rs3389150374	274	R>S	No	EVA
rs3389122649	275	T>R	No	EVA
rs3389138857	297	H>L	No	EVA
rs3389122668	298	Y>*	No	EVA
rs3389150383	334	G>D	No	EVA
rs3389163340	341	Y>F	No	EVA
rs3389122723	349	K>N	No	EVA
rs3402071446	361	W>R	No	EVA
rs3389126950	384	L>F	No	EVA
rs3389150371	418	L>I	No	EVA
rs3389145062	456	R>Q	No	EVA
rs3389147085	459	F>L	No	EVA
rs3389161789	464	L>P	No	EVA
rs3389154793	478	L>P	No	EVA
rs3389150570	495	V>M	No	EVA
rs3389138835	498	N>K	No	EVA
rs3389147090	552	L>M	No	EVA
rs3389090460	567	R>G	No	EVA

No associated diseases with Q03526

11 regional properties for Q03526

Type	Name	Position	InterPro Accession
domain	C2 domain	354 - 474	IPR000008
domain	Protein kinase domain	658 - 917	IPR000719
domain	AGC-kinase, C-terminal	918 - 985	IPR000961
active_site	Serine/threonine-protein kinase, active site	779 - 791	IPR008271
domain	HR1 rho-binding domain	33 - 110	IPR011072-1
domain	HR1 rho-binding domain	121 - 205	IPR011072-2
domain	HR1 rho-binding domain	207 - 287	IPR011072-3
binding_site	Protein kinase, ATP binding site	664 - 687	IPR017441
domain	Protein kinase, C-terminal	938 - 980	IPR017892
domain	Serine/threonine-protein kinase N, first HR1 domain	42 - 107	IPR037313
domain	Serine/threonine-protein kinase N, C2 domain	391 - 474	IPR037784

Functions

		Description
EC Number	2.7.10.2	Protein-tyrosine kinases
Subcellular Localization	Cytoplasm Nucleus	Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

4 GO annotations of cellular component

Name	Definition
cell-cell junction	A cell junction that forms a connection between two or more cells of an organism; excludes direct cytoplasmic intercellular bridges, such as ring canals in insects.
cytosol	The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
nucleus	A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated. In most cells, the nucleus contains all of the cell's chromosomes except the organellar chromosomes, and is the site of RNA synthesis and processing. In some species, or in specialized cell types, RNA metabolism or DNA replication may be absent.
plasma membrane	The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.

3 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
metal ion binding	Binding to a metal ion.
non-membrane spanning protein tyrosine kinase activity	Catalysis of the reaction

9 GO annotations of biological process

Name	Definition
activation of phospholipase C activity	The initiation of the activity of the inactive enzyme phospolipase C as the result of The series of molecular signals generated as a consequence of a G protein-coupled receptor binding to its physiological ligand.
adaptive immune response	An immune response mediated by cells expressing specific receptors for antigens produced through a somatic diversification process, and allowing for an enhanced secondary response to subsequent exposures to the same antigen (immunological memory).
B cell receptor signaling pathway	The series of molecular signals initiated by the cross-linking of an antigen receptor on a B cell.
gamma-delta T cell activation	The change in morphology and behavior of a gamma-delta T cell resulting from exposure to a mitogen, cytokine, chemokine, cellular ligand, or an antigen for which it is specific.
intracellular signal transduction	The process in which a signal is passed on to downstream components within the cell, which become activated themselves to further propagate the signal and finally trigger a change in the function or state of the cell.
NK T cell differentiation	The process in which a precursor cell type acquires the specialized features of a NK T cell.
positive regulation of cytokine production	Any process that activates or increases the frequency, rate or extent of production of a cytokine.
protein phosphorylation	The process of introducing a phosphate group on to a protein.
T cell receptor signaling pathway	The series of molecular signals initiated by the cross-linking of an antigen receptor on a T cell.

86 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
A0JNB0	FYN	Tyrosine-protein kinase Fyn	Bos taurus (Bovine)	SS
Q0VBZ0	CSK	Tyrosine-protein kinase CSK	Bos taurus (Bovine)	SS
Q3ZC95	BTK	Tyrosine-protein kinase	Bos taurus (Bovine)	EV SS
P42683	LCK	Proto-oncogene tyrosine-protein kinase LCK	Gallus gallus (Chicken)	SS
P41239	CSK	Tyrosine-protein kinase CSK	Gallus gallus (Chicken)	SS
P00523	SRC	Proto-oncogene tyrosine-protein kinase Src	Gallus gallus (Chicken)	EV
Q02977	YRK	Proto-oncogene tyrosine-protein kinase Yrk	Gallus gallus (Chicken)	SS
Q8JH64	BTK	Tyrosine-protein kinase BTK	Gallus gallus (Chicken)	SS
P09324	YES1	Tyrosine-protein kinase Yes	Gallus gallus (Chicken)	SS
Q05876	FYN	Tyrosine-protein kinase Fyn	Gallus gallus (Chicken)	SS
Q75R65	JAK2	Tyrosine-protein kinase JAK2	Gallus gallus (Chicken)	SS
Q24592	hop	Tyrosine-protein kinase hopscotch	Drosophila melanogaster (Fruit fly)	PR
Q9V9J3	Src42A	Tyrosine-protein kinase Src42A	Drosophila melanogaster (Fruit fly)	SS
P00528	Src64B	Tyrosine-protein kinase Src64B	Drosophila melanogaster (Fruit fly)	SS
P08630	Btk	Tyrosine-protein kinase Btk	Drosophila melanogaster (Fruit fly)	SS
P41240	CSK	Tyrosine-protein kinase CSK	Homo sapiens (Human)	SS
P51451	BLK	Tyrosine-protein kinase Blk	Homo sapiens (Human)	SS
P06239	LCK	Tyrosine-protein kinase Lck	Homo sapiens (Human)	EV
P23458	JAK1	Tyrosine-protein kinase JAK1	Homo sapiens (Human)	SS
P06241	FYN	Tyrosine-protein kinase Fyn	Homo sapiens (Human)	SS
P51813	BMX	Cytoplasmic tyrosine-protein kinase BMX	Homo sapiens (Human)	SS
P12931	SRC	Proto-oncogene tyrosine-protein kinase Src	Homo sapiens (Human)	EV
P09769	FGR	Tyrosine-protein kinase Fgr	Homo sapiens (Human)	SS
P42680	TEC	Tyrosine-protein kinase Tec	Homo sapiens (Human)	SS
O60674	JAK2	Tyrosine-protein kinase JAK2	Homo sapiens (Human)	EV
P42679	MATK	Megakaryocyte-associated tyrosine-protein kinase	Homo sapiens (Human)	SS
P52333	JAK3	Tyrosine-protein kinase JAK3	Homo sapiens (Human)	SS
P07948	LYN	Tyrosine-protein kinase Lyn	Homo sapiens (Human)	SS
P29597	TYK2	Non-receptor tyrosine-protein kinase TYK2	Homo sapiens (Human)	EV
Q13882	PTK6	Protein-tyrosine kinase 6	Homo sapiens (Human)	EV
P08631	HCK	Tyrosine-protein kinase HCK	Homo sapiens (Human)	EV
P07947	YES1	Tyrosine-protein kinase Yes	Homo sapiens (Human)	SS
P42685	FRK	Tyrosine-protein kinase FRK	Homo sapiens (Human)	EV
Q06187	BTK	Tyrosine-protein kinase BTK	Homo sapiens (Human)	EV
Q08881	ITK	Tyrosine-protein kinase ITK/TSK	Homo sapiens (Human)	EV
Q9R117	Tyk2	Non-receptor tyrosine-protein kinase TYK2	Mus musculus (Mouse)	SS
Q62137	Jak3	Tyrosine-protein kinase JAK3	Mus musculus (Mouse)	SS
Q62120	Jak2	Tyrosine-protein kinase JAK2	Mus musculus (Mouse)	EV
P52332	Jak1	Tyrosine-protein kinase JAK1	Mus musculus (Mouse)	SS
P05480	Src	Proto-oncogene tyrosine-protein kinase Src	Mus musculus (Mouse)	EV
P06240	Lck	Proto-oncogene tyrosine-protein kinase LCK	Mus musculus (Mouse)	SS
P14234	Fgr	Tyrosine-protein kinase Fgr	Mus musculus (Mouse)	SS
P16277	Blk	Tyrosine-protein kinase Blk	Mus musculus (Mouse)	SS
P35991	Btk	Tyrosine-protein kinase BTK	Mus musculus (Mouse)	EV
P41241	Csk	Tyrosine-protein kinase CSK	Mus musculus (Mouse)	EV
Q04736	Yes1	Tyrosine-protein kinase Yes	Mus musculus (Mouse)	SS
Q64434	Ptk6	Protein-tyrosine kinase 6	Mus musculus (Mouse)	SS
Q922K9	Frk	Tyrosine-protein kinase FRK	Mus musculus (Mouse)	SS
P48025	Syk	Tyrosine-protein kinase SYK	Mus musculus (Mouse)	SS
P43404	Zap70	Tyrosine-protein kinase ZAP-70	Mus musculus (Mouse)	SS
P25911	Lyn	Tyrosine-protein kinase Lyn	Mus musculus (Mouse)	EV
P39688	Fyn	Tyrosine-protein kinase Fyn	Mus musculus (Mouse)	SS
P08103	Hck	Tyrosine-protein kinase HCK	Mus musculus (Mouse)	SS
P24604	Tec	Tyrosine-protein kinase Tec	Mus musculus (Mouse)	SS
P41242	Matk	Megakaryocyte-associated tyrosine-protein kinase	Mus musculus (Mouse)	SS
Q9QVP9	Ptk2b	Protein-tyrosine kinase 2-beta	Mus musculus (Mouse)	PR
P34152	Ptk2	Focal adhesion kinase 1	Mus musculus (Mouse)	SS
Q99ML2	Tnk1	Non-receptor tyrosine-protein kinase TNK1	Mus musculus (Mouse)	PR
O54967	Tnk2	Activated CDC42 kinase 1	Mus musculus (Mouse)	SS
P70451	Fer	Tyrosine-protein kinase Fer	Mus musculus (Mouse)	PR
Q6J9G1	Styk1	Tyrosine-protein kinase STYK1	Mus musculus (Mouse)	PR
P00520	Abl1	Tyrosine-protein kinase ABL1	Mus musculus (Mouse)	EV
Q62270	Srms	Tyrosine-protein kinase Srms	Mus musculus (Mouse)	SS
Q4JIM5	Abl2	Tyrosine-protein kinase ABL2	Mus musculus (Mouse)	SS
A1Y2K1	FYN	Tyrosine-protein kinase Fyn	Sus scrofa (Pig)	SS
O19064	JAK2	Tyrosine-protein kinase JAK2	Sus scrofa (Pig)	SS
Q62662	Frk	Tyrosine-protein kinase FRK	Rattus norvegicus (Rat)	SS
Q62844	Fyn	Tyrosine-protein kinase Fyn	Rattus norvegicus (Rat)	SS
Q07014	Lyn	Tyrosine-protein kinase Lyn	Rattus norvegicus (Rat)	SS
P50545	Hck	Tyrosine-protein kinase HCK	Rattus norvegicus (Rat)	SS
Q9WUD9	Src	Proto-oncogene tyrosine-protein kinase Src	Rattus norvegicus (Rat)	SS
Q01621	Lck	Proto-oncogene tyrosine-protein kinase LCK	Rattus norvegicus (Rat)	SS
Q6P6U0	Fgr	Tyrosine-protein kinase Fgr	Rattus norvegicus (Rat)	SS
Q62689	Jak2	Tyrosine-protein kinase JAK2	Rattus norvegicus (Rat)	SS
Q63272	Jak3	Tyrosine-protein kinase JAK3	Rattus norvegicus (Rat)	SS
P32577	Csk	Tyrosine-protein kinase CSK	Rattus norvegicus (Rat)	SS
P41243	Matk	Megakaryocyte-associated tyrosine-protein kinase	Rattus norvegicus (Rat)	SS
F1LM93	Yes1	Tyrosine-protein kinase Yes	Rattus norvegicus (Rat)	SS
O45539	src-2	Tyrosine protein-kinase src-2	Caenorhabditis elegans	SS
G5ECJ6	csk-1	Tyrosine-protein kinase csk-1	Caenorhabditis elegans	SS
G5EE56	src-1	Tyrosine protein-kinase src-1	Caenorhabditis elegans	SS
A1A5H8	yes1	Tyrosine-protein kinase yes	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
F1RDG9	fynb	Tyrosine-protein kinase fynb	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
O12990	jak1	Tyrosine-protein kinase JAK1	Danio rerio (Zebrafish) (Brachydanio rerio)	PR
Q1JPZ3	src	Proto-oncogene tyrosine-protein kinase Src	Danio rerio (Zebrafish) (Brachydanio rerio)	SS
Q6EWH2	fyna	Tyrosine-protein kinase fyna	Danio rerio (Zebrafish) (Brachydanio rerio)	SS

10	20	30	40	50	60
MNNFILLEEQ	LIKKSQQKRR	TSPSNFKVRF	FVLTKASLAY	FEDRHGKKRT	LKGSIELSRI
70	80	90	100	110	120
KCVEIVKSDI	SIPCHYKYPF	QTLVYLQVVH	DNYLLYVFAP	DCESRQRWVL	TLKEETRNNN
130	140	150	160	170	180
SLVSKYHPNF	WMDGRWRCCS	QLEKPAVGCA	PYDPSKNASK	KPLPPTPEDN	RRSFQEPEET
190	200	210	220	230	240
LVIALYDYQT	NDPQELALRC	DEEYYLLDSS	EIHWWRVQDK	NGHEGYAPSS	YLVEKSPNNL
250	260	270	280	290	300
ETYEWYNKSI	SRDKAEKLLL	DTGKEGAFMV	RDSRTPGTYT	VSVFTKAIIS	ENPCIKHYHI
310	320	330	340	350	360
KETNDSPKRY	YVAEKYVFDS	IPLLIQYHQY	NGGGLVTRLR	YPVCSWRQKA	PVTAGLRYGK
370	380	390	400	410	420
WVIQPSELTF	VQEIGSGQFG	LVHLGYWLNK	DKVAIKTIQE	GAMSEEDFIE	EAEVMMKLSH
430	440	450	460	470	480
PKLVQLYGVC	LEQAPICLVF	EFMEHGCLSD	YLRSQRGLFA	AETLLGMCLD	VCEGMAYLEK
490	500	510	520	530	540
ACVIHRDLAA	RNCLVGENQV	IKVSDFGMTR	FVLDDQYTSS	TGTKFPVKWA	SPEVFSFSRY
550	560	570	580	590	600
SSKSDVWSFG	VLMWEVFSEG	KIPYENRSNS	EVVEDISTGF	RLYKPRLASC	HVYQIMNHCW
610	620
KEKPEDRPPF	SQLLSQLAEI	AEAGL