AiPD: Autoinhibited Protein Database

Q0VBZ0

Gene name	CSK
Protein name	Tyrosine-protein kinase CSK
Names	EC 2.7.10.2 , C-Src kinase
Species	Bos taurus (Bovine)
KEGG Pathway	bta:509246
EC number	2.7.10.2: Protein-tyrosine kinases
Protein Class

Descriptions

The kinase Csk is the primary negative regulator of the Src‐family kinases (SFKs, e.g., Lck, Fyn, Lyn, Hck, Fgr, Blk, Yes). Csk phosphorylates a tyrosine on the SFK C‐terminal tail that mediates autoinhibition. Csk is recruited to membrane-anchored SFKs and activated allosterically via its SH2 domain, which binds SFK- phosphorylated motifs in CBP/PAG1 (Csk binding protein/phosphoprotein associated with glycosphingolipid- enriched microdomains), Paxillin, Fak, the Dok family, and other tyrosine-phosphorylated proteins. Csk also binds phosphatases, including PTPN12 (PTP‐PEST) and immune‐cell PTPN22 (LYP/Pep), which dephosphorylate SFK activation loop to promote autoinhibition. <br> Purified Csk homodimerizes in competition with PTPN22 binding through an interface that is mediated by symmetrical SH3-SH3 interactions and that overlaps the phosphatase binding footprint. Mutation in SH3 impairing homodimerization enhances PTPN22 binding.

Autoinhibitory domains (AIDs)

9-70 (SH3 domain) SS

Target domain	9-70 (SH3 domain)
Relief mechanism	Partner binding
Assay

AID

9-70 (SH3 domain)

Target domain

9-70 (SH3 domain)

Relief mechanism

Partner binding (Binding of SFKs to SH2 domain)

Assay

80-171 (SH2 domain) SS

Target domain	195-444 (Protein kinase domain)
Relief mechanism	Ligand binding
Assay

AID

80-171 (SH2 domain)

Target domain

195-444 (Protein kinase domain)

Relief mechanism

Ligand binding (Phosphotyrosine-containing peptide binding)

Assay

Accessory elements

331-351 (Activation loop from InterPro)

Target domain	195-449 (Protein kinase domain)
Relief mechanism
Assay

References

Brian BF 4th et al. (2022) "SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding", Scientific reports, 12, 5875

Ghose R et al. (2001) "A novel, specific interaction involving the Csk SH3 domain and its natural ligand", Nature structural biology, 8, 998-1004

Hong E et al. (2004) "Solution structure and backbone dynamics of the non-receptor protein-tyrosine kinase-6 Src homology 2 domain", The Journal of biological chemistry, 279, 29700-8

Ko S et al. (2009) "Structural basis of the auto-inhibition mechanism of nonreceptor tyrosine kinase PTK6", Biochemical and biophysical research communications, 384, 236-42

Qiu H et al. (2002) "Regulation of the nonreceptor tyrosine kinase Brk by autophosphorylation and by autoinhibition", The Journal of biological chemistry, 277, 34634-41

Autoinhibited structure

Activated structure

1 structures for Q0VBZ0

Entry ID	Method	Resolution	Chain	Position	Source
AF-Q0VBZ0-F1	Predicted				AlphaFoldDB

108 variants for Q0VBZ0

Variant ID(s)	Position	Change	Diseaes Association	Provenance
rs449556149	8	W>G	No	EVA
rs876411981	18	Y>D	No	EVA
rs3423493126	22	G>S	No	EVA
rs135375252	41	V>G	No	EVA
rs471027001	89	R>L	No	EVA
rs876557356	101	T>A	No	EVA
rs475346281	104	F>V	No	EVA
rs455028697	106	V>G	No	EVA
rs876356682	148	N>T	No	EVA
rs457765406	157	T>P	No	EVA
rs444022301	158	S>P	No	EVA
rs475368891	159	D>H	No	EVA
rs462068779	160	A>P	No	EVA
rs441837038	160	A>V	No	EVA
rs473085716	162	G>V	No	EVA
rs471962608	176	T>P	No	EVA
rs451660879	183	F>S	No	EVA
rs437997130	184	F>S	No	EVA
rs469327586	185	R>H	No	EVA
rs439570821	191	N>D	No	EVA
rs471316086	194	D>V	No	EVA
rs457592228	195	L>R	No	EVA
rs437391975	198	L>V	No	EVA
rs468569697	205	E>G	No	EVA
rs468569697	205	E>V	No	EVA
rs454498580	208	D>Y	No	EVA
rs441378056	249	V>G	No	EVA
rs472806707	260	S>G	No	EVA
rs452137299	265	V>F	No	EVA
rs476293208	266	T>P	No	EVA
rs456167744	268	Y>S	No	EVA
rs435970709	269	M>R	No	EVA
rs453981329	271	K>R	No	EVA
rs477998764	273	S>R	No	EVA
rs464263680	275	V>G	No	EVA
rs450403043	278	L>V	No	EVA
rs481581030	279	R>P	No	EVA
rs461890368	280	S>P	No	EVA
rs441837076	281	R>P	No	EVA
rs459512624	286	L>H	No	EVA
rs471924065	291	L>R	No	EVA
rs444462039	293	K>N	No	EVA
rs466034560	298	V>G	No	EVA
rs445894130	300	E>D	No	EVA
rs477324535	301	A>V	No	EVA
rs463586715	306	E>*	No	EVA
rs482364507	329	K>Q	No	EVA
rs462198190	340	S>P	No	EVA
rs442007042	342	T>P	No	EVA
rs473398013	344	D>A	No	EVA
rs460017398	350	V>I	No	EVA
rs439908265	352	W>R	No	EVA
rs471090624	353	T>A	No	EVA
rs452127625	383	G>A	No	EVA
rs472266159	383	G>W	No	EVA
rs431909778	387	Y>H	No	EVA
rs459111670	393	K>E	No	EVA
rs445446822	397	P>T	No	EVA
rs482759572	398	R>W	No	EVA
rs442451489	399	V>A	No	EVA
rs442451489	399	V>E	No	EVA
rs442451489	399	V>G	No	EVA
rs473766995	401	K>M	No	EVA
rs460476255	402	G>R	No	EVA
rs440323286	404	K>E	No	EVA
rs471700222	405	M>L	No	EVA
rs437709853	406	D>E	No	EVA
rs451444469	406	D>V	No	EVA
rs476519902	407	A>T	No	EVA
rs467769587	408	P>L	No	EVA
rs436412011	408	P>T	No	EVA
rs434322558	409	D>A	No	EVA
rs465663636	409	D>E	No	EVA
rs434322558	409	D>G	No	EVA
rs445464946	410	G>S	No	EVA
rs483180071	413	P>T	No	EVA
rs469087741	418	V>G	No	EVA
rs480327171	422	C>G	No	EVA
rs460134000	423	W>G	No	EVA
rs439985551	424	H>L	No	EVA
rs439985551	424	H>P	No	EVA
rs478156402	425	L>V	No	EVA
rs457837938	426	D>N	No	EVA
rs444211889	426	D>V	No	EVA
rs455349369	427	A>G	No	EVA
rs475377989	427	A>P	No	EVA
rs442928457	428	A>P	No	EVA
rs474319184	429	T>P	No	EVA
rs433925309	432	S>P	No	EVA
rs465675877	434	L>R	No	EVA
rs451990642	435	Q>K	No	EVA
rs438232304	435	Q>R	No	EVA
rs469606168	436	L>P	No	EVA
rs480421452	439	Q>E	No	EVA
rs466637068	441	E>A	No	EVA
rs446414913	443	I>L	No	EVA
rs477570657	443	I>S	No	EVA
rs477570657	443	I>T	No	EVA
rs457899542	445	T>P	No	EVA
rs444324256	446	H>R	No	EVA
rs481906013	447	E>*	No	EVA
rs461814682	447	E>D	No	EVA
rs481906013	447	E>K	No	EVA
rs441805950	448	L>P	No	EVA
rs454165366	449	H>D	No	EVA
rs876030187	449	H>P	No	EVA
rs471766628	450	L>P	No	EVA
rs451702425	451	L>S	No	EVA

No associated diseases with Q0VBZ0

6 regional properties for Q0VBZ0

Type	Name	Position	InterPro Accession
domain	Pleckstrin homology domain	370 - 475	IPR001849
domain	FERM central domain	281 - 355	IPR019748-1
domain	FERM central domain	471 - 570	IPR019748-2
domain	Band 4.1 domain	91 - 570	IPR019749
domain	Kindlin/fermitin, PH domain	370 - 493	IPR037837
domain	Kindlin-2, N-terminal	10 - 95	IPR040790

Functions

		Description
EC Number	2.7.10.2	Protein-tyrosine kinases
Subcellular Localization	Cytoplasm Cell membrane	Mainly cytoplasmic, also present in lipid rafts
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

2 GO annotations of cellular component

Name	Definition
cytoplasm	The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.
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

4 GO annotations of biological process

Name	Definition
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).
adherens junction organization	A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of an adherens junction. An adherens junction is a cell-cell junction composed of the epithelial cadherin-catenin complex at which the cytoplasmic face of the plasma membrane is attached to actin filaments.
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.
regulation of Fc receptor mediated stimulatory signaling pathway	Any process that modulates the rate, frequency or extent of the Fc receptor mediated stimulatory signaling pathway..

79 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
A0JNB0	FYN	Tyrosine-protein kinase Fyn	Bos taurus (Bovine)	SS
Q3ZC95	BTK	Tyrosine-protein kinase	Bos taurus (Bovine)	EV SS
Q17R13	TNK2	Activated CDC42 kinase 1	Bos taurus (Bovine)	SS
P42683	LCK	Proto-oncogene tyrosine-protein kinase LCK	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
P41239	CSK	Tyrosine-protein kinase CSK	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
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
Q08881	ITK	Tyrosine-protein kinase ITK/TSK	Homo sapiens (Human)	EV
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
P41240	CSK	Tyrosine-protein kinase CSK	Homo sapiens (Human)	SS
Q9R117	Tyk2	Non-receptor tyrosine-protein kinase TYK2	Mus musculus (Mouse)	SS
P08103	Hck	Tyrosine-protein kinase HCK	Mus musculus (Mouse)	SS
P16277	Blk	Tyrosine-protein kinase Blk	Mus musculus (Mouse)	SS
Q62270	Srms	Tyrosine-protein kinase Srms	Mus musculus (Mouse)	SS
Q64434	Ptk6	Protein-tyrosine kinase 6	Mus musculus (Mouse)	SS
P05480	Src	Proto-oncogene tyrosine-protein kinase Src	Mus musculus (Mouse)	EV
P14234	Fgr	Tyrosine-protein kinase Fgr	Mus musculus (Mouse)	SS
P35991	Btk	Tyrosine-protein kinase BTK	Mus musculus (Mouse)	EV
P25911	Lyn	Tyrosine-protein kinase Lyn	Mus musculus (Mouse)	EV
Q62137	Jak3	Tyrosine-protein kinase JAK3	Mus musculus (Mouse)	SS
Q62120	Jak2	Tyrosine-protein kinase JAK2	Mus musculus (Mouse)	EV
P06240	Lck	Proto-oncogene tyrosine-protein kinase LCK	Mus musculus (Mouse)	SS
P24604	Tec	Tyrosine-protein kinase Tec	Mus musculus (Mouse)	SS
Q04736	Yes1	Tyrosine-protein kinase Yes	Mus musculus (Mouse)	SS
P39688	Fyn	Tyrosine-protein kinase Fyn	Mus musculus (Mouse)	SS
P52332	Jak1	Tyrosine-protein kinase JAK1	Mus musculus (Mouse)	SS
Q03526	Itk	Tyrosine-protein kinase ITK/TSK	Mus musculus (Mouse)	SS
P41242	Matk	Megakaryocyte-associated tyrosine-protein kinase	Mus musculus (Mouse)	SS
Q922K9	Frk	Tyrosine-protein kinase FRK	Mus musculus (Mouse)	SS
P41241	Csk	Tyrosine-protein kinase CSK	Mus musculus (Mouse)	EV
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
P41243	Matk	Megakaryocyte-associated tyrosine-protein kinase	Rattus norvegicus (Rat)	SS
F1LM93	Yes1	Tyrosine-protein kinase Yes	Rattus norvegicus (Rat)	SS
P32577	Csk	Tyrosine-protein kinase CSK	Rattus norvegicus (Rat)	SS
O45539	src-2	Tyrosine protein-kinase src-2	Caenorhabditis elegans	SS
G5EE56	src-1	Tyrosine protein-kinase src-1	Caenorhabditis elegans	SS
Q8I7I5	rol-3	Protein roller-3	Caenorhabditis elegans	PR
O16262	nipi-4	Protein nipi-4	Caenorhabditis elegans	PR
G5ECJ6	csk-1	Tyrosine-protein kinase csk-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
MSAIQAAWPS	GTECIAKYNF	HGTAEQDLPF	CKGDVLTIVA	VTKDPNWYKA	KNKVGREGII
70	80	90	100	110	120
PANYVQKREG	VKAGTKLSLM	PWFHGKITRE	QAERLLCPPE	TGLFLVREST	NYPGDYTLCV
130	140	150	160	170	180
SCDGKVEHYR	IMYHASKLSI	DEEVYFENLM	QLVEHYTSDA	DGLCTRLIKP	KVMEGTVAAQ
190	200	210	220	230	240
DEFFRSGWAL	NMKDLKLLQT	IGKGEFGDVM	LGDYRGNKVA	VKCIKNDATA	QAFLAEASVM
250	260	270	280	290	300
TQLRHSNLVQ	LLGVIVEEKS	GLYIVTEYMA	KGSLVDYLRS	RGRSVLGGDC	LLKFSLDVCE
310	320	330	340	350	360
AMEYLEGNNF	VHRDLAARNV	LVSEDNVAKV	SDFGLTKEAS	STQDTGKLPV	KWTAPEALRE
370	380	390	400	410	420
KKFSTKSDVW	SFGILLWEIY	SFGRVPYPRI	PLKDVVPRVE	KGYKMDAPDG	CPPAVYEVMK
430	440
NCWHLDAATR	PSFLQLREQL	ERIKTHELHL