SRC: Difference between revisions
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< | <StructureSection load='2src' size='350' side='right' scene='' caption='Human C-SRC complex with AMP-PNP [[2src]]'> | ||
The ''c-src | The '''c-src proto-oncogene''' encodes a protein tyrosine kinase. The ''v-src'' oncogene of the Rous sarcoma virus encodes a mutated, activated form of this enzyme. In particular, the virally encoded V-SRC protein lacks the carboxyl-terminus of the normal C-SRC protein. Phosphopeptide mapping and site-directed mutagenesis revealed the importance of two tyrosine (TYR) residues that are critical for the activity and regulation of C-SRC, TYR416 and TYR527. Insertional mutagenesis and comparisons with other proteins revealed the presence of three highly conserved '''S'''RC '''H'''omology domains, SH1, SH2, and SH3. | ||
<scene name='User:Joseph_Lipsick/SRC/Sh1/5'>SH1</scene> comprises the catalytic protein kinase. Within SH1 is <scene name='User:Joseph_Lipsick/SRC/Tyr416/2'>TYR416</scene> which hinders access to the active site. Phosphorylation of TYR416 induces a conformational change that is required for full kinase activity (see below). In contrast, when <scene name='User:Joseph_Lipsick/SRC/Phospho-tyr527/4'>TYR527</scene>, which lies carboxy-terminal to the SH1 domain is phosphorylated, the kinase is inactive. SH2 domains were shown to bind to peptides containing phosphotyrosine. In particular, the <scene name='User:Joseph_Lipsick/SRC/Sh2/2'>SH2</scene> domain of C-SRC binds to phospho-TYR527. Although this binding is reversible, the bound state predominates. This bound state prevents the kinase from phosphorylating substrates. Therefore, phosphorylation of TYR527 greatly diminishes autophosphorylation of TYR416. In this regard, the phosphorylation of TYR527 by another protein kinase (CSK) results in the inactivation of C-SRC. Conversely, removal of TYR527 by truncation (as in V-SRC) or by substitution with PHE (by site-directed mutagenesis) causes constitutive activation of the kinase. Similarly, the physiological dephosphorylation of TYR527 results in an <scene name='User:Joseph_Lipsick/SRC/Activated_c-src/6'>opening</scene> of the protein structure by release of the SH2 domain. The loop which contains TYR416 and occludes the active site of the SH1 kinase domain is first autophosphorylated. phospho-TYR416 then alters the conformation of this loop, resulting in a dramatic increase in protein kinase activity. SH3 domains were shown to bind to peptides with multiple adjacent proline residues. The <scene name='User:Joseph_Lipsick/SRC/Sh3/4'>SH3</scene> domain of C-SRC binds to the SH2 domain of C-SRC, thereby helping to stabilize the conformation of the entire protein. The SH2 domain of C-SRC can bind to phospho-TYR on other proteins (e.g. an activated receptor tyrosine kinase like PDGF-R), thereby opening the C-SRC protein conformation, exposing phospho-TYR527 to protein phosphatases, and resulting in activation of C-SRC. In some cases interactions of the SH3 domain with other proteins can also facilitate this activation process. | <scene name='User:Joseph_Lipsick/SRC/Sh1/5'>SH1</scene> comprises the catalytic protein kinase. Within SH1 is <scene name='User:Joseph_Lipsick/SRC/Tyr416/2'>TYR416</scene> which hinders access to the active site. Phosphorylation of TYR416 induces a conformational change that is required for full kinase activity (see below). In contrast, when <scene name='User:Joseph_Lipsick/SRC/Phospho-tyr527/4'>TYR527</scene>, which lies carboxy-terminal to the SH1 domain is phosphorylated, the kinase is inactive. SH2 domains were shown to bind to peptides containing phosphotyrosine. In particular, the <scene name='User:Joseph_Lipsick/SRC/Sh2/2'>SH2</scene> domain of C-SRC binds to phospho-TYR527. Although this binding is reversible, the bound state predominates. This bound state prevents the kinase from phosphorylating substrates. Therefore, phosphorylation of TYR527 greatly diminishes autophosphorylation of TYR416. In this regard, the phosphorylation of TYR527 by another protein kinase (CSK) results in the inactivation of C-SRC. Conversely, removal of TYR527 by truncation (as in V-SRC) or by substitution with PHE (by site-directed mutagenesis) causes constitutive activation of the kinase. Similarly, the physiological dephosphorylation of TYR527 results in an <scene name='User:Joseph_Lipsick/SRC/Activated_c-src/6'>opening</scene> of the protein structure by release of the SH2 domain. The loop which contains TYR416 and occludes the active site of the SH1 kinase domain is first autophosphorylated. phospho-TYR416 then alters the conformation of this loop, resulting in a dramatic increase in protein kinase activity. SH3 domains were shown to bind to peptides with multiple adjacent proline residues. The <scene name='User:Joseph_Lipsick/SRC/Sh3/4'>SH3</scene> domain of C-SRC binds to the SH2 domain of C-SRC, thereby helping to stabilize the conformation of the entire protein. The SH2 domain of C-SRC can bind to phospho-TYR on other proteins (e.g. an activated receptor tyrosine kinase like PDGF-R), thereby opening the C-SRC protein conformation, exposing phospho-TYR527 to protein phosphatases, and resulting in activation of C-SRC. In some cases interactions of the SH3 domain with other proteins can also facilitate this activation process. | ||
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<scene name='User:Joseph_Lipsick/SRC/Tyr416/2'>TYR416</scene> | <scene name='User:Joseph_Lipsick/SRC/Tyr416/2'>TYR416</scene> | ||
<scene name='User:Joseph_Lipsick/SRC/Phospho-tyr527/4'>TYR527</scene> | <scene name='User:Joseph_Lipsick/SRC/Phospho-tyr527/4'>TYR527</scene> | ||
</StructureSection> | |||
==3D structures of Proto-oncogene tyrosine-protein kinase SRC== | ==3D structures of Proto-oncogene tyrosine-protein kinase SRC== | ||
[[ | [[Tyrosine kinase]] | ||
==Additional Resources== | ==Additional Resources== | ||