AiPD: Autoinhibited Protein Database

P09324

Gene name	YES1 (YES)
Protein name	Tyrosine-protein kinase Yes
Names	EC 2.7.10.2 , p61-Yes
Species	Gallus gallus (Chicken)
KEGG Pathway	gga:396238
EC number	2.7.10.2: Protein-tyrosine kinases
Protein Class

Descriptions

Lyn, a Src family tyrosine kinase, plays an important role in relaying signals originating from a number of hematopoietic cell surface receptors such as B-cell receptor. Stimulation of B-lymphocytes, by engagement of the B-cell receptor, results in rapid tyrosine phosphorylation and activation of Lyn. Lyn contains an N-terminal domain, Src homology 2 (SH2) domain, Src homology 3 (SH3) domain, a protein kinase domain and a C-terminal regulatory domain. Two major consensus tyrosine phosphorylation sites are conserved in Src family kinases: (1) the autophosphorylation site in the protein kinase domain and (2) the tyrosine phosphorylation site in the C-terminal regulatory tail. Phosphorylation of the C-terminal tyrosine in Src family kinases negatively regulates their activity. The intracellular interaction between the phosphorylated C-terminal tyrosine and the SH2 domain stabilizes the inactive conformation of the kinase (autoinhibition state), while the autophosphorylation in the protein kinase domain (pY397) relieves the conformational constraint that prevents binding of the substrate peptide to the active site of the kinase.

Autoinhibitory domains (AIDs)

89-150 (SH3 domain) SS

Target domain	275-528 (Protein kinase domain)
Relief mechanism	Partner binding, Ligand binding
Assay

AID

89-150 (SH3 domain)

Target domain

275-528 (Protein kinase domain)

Relief mechanism

Partner binding (HIV-1 binding to SH3), Ligand binding (ligand binding to SH3 domain)

Assay

156-253 (SH2 domain) SS

Target domain	275-528 (Protein kinase domain)
Relief mechanism	PTM
Assay

AID

156-253 (SH2 domain)

Target domain

275-528 (Protein kinase domain)

Relief mechanism

PTM (Phosphorylation of tyrosine residues on C-terminal regulatory tail)

Assay

254-274 (SH2-kinase linker) SS

Target domain	275-528 (Protein kinase domain)
Relief mechanism	Ligand binding
Assay

AID

254-274 (SH2-kinase linker)

Target domain

275-528 (Protein kinase domain)

Relief mechanism

Ligand binding (ligand binding to SH3 domain)

Assay

529-541 (C-terminal regulatory tail) SS

Target domain	275-528 (Protein kinase domain)
Relief mechanism	PTM
Assay

AID

529-541 (C-terminal regulatory tail)

Target domain

275-528 (Protein kinase domain)

Relief mechanism

PTM (Phosphorylation of tyrosine residues on C-terminal regulatory tail)

Assay

Accessory elements

411-435 (Activation loop from InterPro)

Target domain	275-528 (Protein kinase domain)
Relief mechanism
Assay

411-435 (Activation loop from InterPro)

Target domain	275-528 (Protein kinase domain)
Relief mechanism
Assay

References

Yeon JH et al. (2016) "Systems-wide Identification of cis-Regulatory Elements in Proteins", Cell systems, 2, 89-100

Wang Q et al. (2010) "Multicolor monitoring of dysregulated protein kinases in chronic myelogenous leukemia", ACS chemical biology, 5, 887-95

Sotirellis N et al. (1995) "Autophosphorylation induces autoactivation and a decrease in the Src homology 2 domain accessibility of the Lyn protein kinase", The Journal of biological chemistry, 270, 29773-80

Williams NK et al. (2009) "Crystal structures of the Lyn protein tyrosine kinase domain in its Apo- and inhibitor-bound state", The Journal of biological chemistry, 284, 284-291

Williams JC et al. (1997) "The 2.35 A crystal structure of the inactivated form of chicken Src: a dynamic molecule with multiple regulatory interactions", Journal of molecular biology, 274, 757-75

Boggon TJ et al. (2004) "Structure and regulation of Src family kinases", Oncogene, 23, 7918-27

Meng Y et al. (2014) "Locking the active conformation of c-Src kinase through the phosphorylation of the activation loop", Journal of molecular biology, 426, 423-35

Register AC et al. (2014) "SH2-catalytic domain linker heterogeneity influences allosteric coupling across the SFK family", Biochemistry, 53, 6910-23

Laham LE et al. (2000) "The activation loop in Lck regulates oncogenic potential by inhibiting basal kinase activity and restricting substrate specificity", Oncogene, 19, 3961-70

Furlan G et al. (2014) "Phosphatase CD45 both positively and negatively regulates T cell receptor phosphorylation in reconstituted membrane protein clusters", The Journal of biological chemistry, 289, 28514-25

Engen JR et al. (2008) "Structure and dynamic regulation of Src-family kinases", Cellular and molecular life sciences : CMLS, 65, 3058-73

Alvarado JJ et al. (2010) "Crystal structure of the Src family kinase Hck SH3-SH2 linker regulatory region supports an SH3-dominant activation mechanism", The Journal of biological chemistry, 285, 35455-61

Schindler T et al. (1999) "Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor", Molecular cell, 3, 639-48

Kükenshöner T et al. (2017) "Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies", Journal of molecular biology, 429, 1364-1380

Autoinhibited structure

Activated structure

1 structures for P09324

Entry ID	Method	Resolution	Chain	Position	Source
AF-P09324-F1	Predicted				AlphaFoldDB

No variants for P09324

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
No variants for P09324

No associated diseases with P09324

8 regional properties for P09324

Type	Name	Position	InterPro Accession
domain	Protein kinase domain	275 - 528	IPR000719
domain	SH2 domain	154 - 253	IPR000980
domain	Serine-threonine/tyrosine-protein kinase, catalytic domain	276 - 524	IPR001245
domain	SH3 domain	89 - 150	IPR001452
active_site	Tyrosine-protein kinase, active site	390 - 402	IPR008266
binding_site	Protein kinase, ATP binding site	281 - 303	IPR017441
domain	Tyrosine-protein kinase, catalytic domain	275 - 524	IPR020635
domain	Tyrosine-protein kinase Yes, SH3 domain	92 - 149	IPR035751

Functions

		Description
EC Number	2.7.10.2	Protein-tyrosine kinases
Subcellular Localization	Cell membrane Cytoplasm, cytoskeleton, microtubule organizing center, centrosome Cytoplasm, cytosol
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

4 GO annotations of cellular component

Name	Definition
centrosome	A structure comprised of a core structure (in most organisms, a pair of centrioles) and peripheral material from which a microtubule-based structure, such as a spindle apparatus, is organized. Centrosomes occur close to the nucleus during interphase in many eukaryotic cells, though in animal cells it changes continually during the cell-division cycle.
cytosol	The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
extrinsic component of cytoplasmic side of plasma membrane	The component of a plasma membrane consisting of gene products and protein complexes that are loosely bound to its cytoplasmic surface, but not integrated into the hydrophobic region.
Golgi apparatus	A membrane-bound cytoplasmic organelle of the endomembrane system that further processes the core oligosaccharides (e.g. N-glycans) added to proteins in the endoplasmic reticulum and packages them into membrane-bound vesicles. The Golgi apparatus operates at the intersection of the secretory, lysosomal, and endocytic pathways.

6 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
enzyme binding	Binding to an enzyme, a protein with catalytic activity.
non-membrane spanning protein tyrosine kinase activity	Catalysis of the reaction
phosphotyrosine residue binding	Binding to a phosphorylated tyrosine residue within a protein.
signaling receptor binding	Binding to one or more specific sites on a receptor molecule, a macromolecule that undergoes combination with a hormone, neurotransmitter, drug or intracellular messenger to initiate a change in cell function.
transmembrane transporter binding	Binding to a transmembrane transporter, a protein or protein complex that enables the transfer of a substance, usually a specific substance or a group of related substances, from one side of a membrane to the other.

4 GO annotations of biological process

Name	Definition
cell differentiation	The cellular developmental process in which a relatively unspecialized cell, e.g. embryonic or regenerative cell, acquires specialized structural and/or functional features that characterize a specific cell. Differentiation includes the processes involved in commitment of a cell to a specific fate and its subsequent development to the mature state.
innate immune response	Innate immune responses are defense responses mediated by germline encoded components that directly recognize components of potential pathogens.
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.
transmembrane receptor protein tyrosine kinase signaling pathway	The series of molecular signals initiated by an extracellular ligand binding to a receptor on the surface of the target cell where the receptor possesses tyrosine kinase activity, and ending with the regulation of a downstream cellular process, e.g. transcription.

81 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
Q75R65	JAK2	Tyrosine-protein kinase JAK2	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
F1N9Y5	SYK	Tyrosine-protein kinase SYK	Gallus gallus (Chicken)	SS
P41239	CSK	Tyrosine-protein kinase CSK	Gallus gallus (Chicken)	SS
Q00944	PTK2	Focal adhesion kinase 1	Gallus gallus (Chicken)	EV
P42683	LCK	Proto-oncogene tyrosine-protein kinase LCK	Gallus gallus (Chicken)	SS
Q05876	FYN	Tyrosine-protein kinase Fyn	Gallus gallus (Chicken)	SS
Q8JH64	BTK	Tyrosine-protein kinase BTK	Gallus gallus (Chicken)	SS
Q24592	hop	Tyrosine-protein kinase hopscotch	Drosophila melanogaster (Fruit fly)	PR
P08630	Btk	Tyrosine-protein kinase Btk	Drosophila melanogaster (Fruit fly)	SS
P00528	Src64B	Tyrosine-protein kinase Src64B	Drosophila melanogaster (Fruit fly)	SS
Q9V9J3	Src42A	Tyrosine-protein kinase Src42A	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
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
P42685	FRK	Tyrosine-protein kinase FRK	Homo sapiens (Human)	EV
Q06187	BTK	Tyrosine-protein kinase BTK	Homo sapiens (Human)	EV
P07947	YES1	Tyrosine-protein kinase Yes	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
P41241	Csk	Tyrosine-protein kinase CSK	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
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
Q04736	Yes1	Tyrosine-protein kinase Yes	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
G5ECJ6	csk-1	Tyrosine-protein kinase csk-1	Caenorhabditis elegans	SS
O45539	src-2	Tyrosine protein-kinase src-2	Caenorhabditis elegans	SS
G5EE56	src-1	Tyrosine protein-kinase src-1	Caenorhabditis elegans	SS
O22558	STY8	Serine/threonine-protein kinase STY8	Arabidopsis thaliana (Mouse-ear cress)	PR
Q8RWL6	STY17	Serine/threonine-protein kinase STY17	Arabidopsis thaliana (Mouse-ear cress)	PR
F4JTP5	STY46	Serine/threonine-protein kinase STY46	Arabidopsis thaliana (Mouse-ear cress)	PR
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
A1A5H8	yes1	Tyrosine-protein kinase yes	Danio rerio (Zebrafish) (Brachydanio rerio)	SS

10	20	30	40	50	60
MGCIKSKEDK	GPAMKYRTDN	TPEPISSHVS	HYGSDSSQAT	QSPAIKGSAV	NFNSHSMTPF
70	80	90	100	110	120
GGPSGMTPFG	GASSSFSAVP	SPYPSTLTGG	VTVFVALYDY	EARTTDDLSF	KKGERFQIIN
130	140	150	160	170	180
NTEGDWWEAR	SIATGKTGYI	PSNYVAPADS	IQAEEWYFGK	MGRKDAERLL	LNPGNQRGIF
190	200	210	220	230	240
LVRESETTKG	AYSLSIRDWD	EVRGDNVKHY	KIRKLDNGGY	YITTRAQFES	LQKLVKHYRE
250	260	270	280	290	300
HADGLCHKLT	TVCPTVKPQT	QGLAKDAWEI	PRESLRLEVK	LGQGCFGEVW	MGTWNGTTKV
310	320	330	340	350	360
AIKTLKPGTM	MPEAFLQEAQ	IMKKLRHDKL	VPLYAVVSEE	PIYIVTEFMT	KGSLLDFLKE
370	380	390	400	410	420
GEGKFLKLPQ	LVDMAAQIAD	GMAYIERMNY	IHRDLRAANI	LVGDNLVCKI	ADFGLARLIE
430	440	450	460	470	480
DNEYTARQGA	KFPIKWTAPE	AALYGRFTIK	SDVWSFGILL	TELVTKGRVP	YPGMVNREVL
490	500	510	520	530	540
EQVERGYRMP	CPQGCPESLH	ELMKLCWKKD	PDERPTFEYI	QSFLEDYFTA	TEPQYQPGDN

L

Descriptions

Annotation based on sequence homology with P25911

Autoinhibitory domains (AIDs)

Accessory elements

411-435 (Activation loop from InterPro)

411-435 (Activation loop from InterPro)

References

Autoinhibited structure

Activated structure

1 structures for P09324

No variants for P09324

No associated diseases with P09324

8 regional properties for P09324

Functions

4 GO annotations of cellular component

6 GO annotations of molecular function

4 GO annotations of biological process

81 homologous proteins in AiPD