Proto-oncogene tyrosine-protein kinase

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{{STRUCTURE_1fmk| PDB=1fmk | SIZE=400| SCENE= |right| CAPTION=Human proto-oncogene tyrosine-protein kinase Src kinase, SH2, SH3, C terminal domains with phosphotyrosine, [[1fmk]] }}
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<StructureSection load="3geq" size="400" color="" frame="true" spin="on" Scene= align="right" caption='Proto-oncogene tyrosine-protein kinase Src, [[3geq]]' >
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Non-receptor '''proto-oncogene tyrosine-protein kinase''' (NTPK) are enzymes which transfer a phosphate group from ATP to proteins. For details of Proto-oncogene tyrosine-protein kinase SRC see [[SRC]].
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Non-receptor '''proto-oncogene tyrosine-protein kinase''' (NTPK) are enzymes which transfer a phosphate group from ATP to proteins. Protein tyrosine kinases are critical cell signaling enzymes. These enzymes have a highly conserved Arg residue in their catalytic loop which is present two residues or four residues downstream from an absolutely conserved Asp catalytic base. Prior studies on protein tyrosine kinases Csk and Src revealed the potential for chemical rescue of catalytically deficient mutant kinases (Arg to Ala mutations) by small diamino compounds, particularly imidazole; however, the potency and efficiency of rescue was greater for Src. This current study further examines the structural and kinetic basis of rescue for mutant Src as compared to mutant Abl tyrosine kinase. An X-ray crystal structure of R388A Src revealed the surprising finding that a histidine residue of the N-terminus of a symmetry-related kinase inserts into the active site of the adjacent Src and mimics the hydrogen-bonding pattern seen in wild-type protein tyrosine kinases. Abl R367A shows potent and efficient rescue more comparable to Src, even though its catalytic loop is more like that of Csk. Various enzyme redesigns of the active sites indicate that the degree and specificity of rescue are somewhat flexible, but the overall properties of the enzymes and rescue agents play an overarching role. The newly discovered rescue agent 2-aminoimidazole is about as efficient as imidazole in rescuing R/A Src and Abl. Rate vs pH studies with these imidazole analogues suggest that the protonated imidazolium is the preferred form for chemical rescue, consistent with structural models. The efficient rescue seen with mutant Abl points to the potential of this approach to be used effectively to analyze Abl phosphorylation pathways in cells. [http://www.ncbi.nlm.nih.gov/pubmed/19260709 Ref. 1]
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Src from Gallus gallus contains 1 protein kinase domain, 1 SH2 domain, and 1 SH3 domain. 3GEQ becomes activated when its major tyrosine phosphorylation site is not phosphorylated. Phosphorylation occurs on Tyr-527 by c-Src kinase (CSK); the phosphorylated form is termed pp60c-src. The phosphorylated tail interacts with the SH2 domain thereby repressing kinase activity. It can also be activated by point mutations as well as by truncations at the C-terminal end or by other mutations.
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Its subunit structure forms a complex with polyoma virus middle T antigen and interacts with AFAP-110. Interacts with IGF2BP1 [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=16306994 Ref. 3]. Additionally, it is widely expressed to high levels, and with a high degree of kinase activity in certain fully differentiated cells such as neurons, platelets and macrophages. Isoform 1 is widely expressed. Isoform 2 is expressed only in the muscle.
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For details of Proto-oncogene tyrosine-protein kinase SRC see [[SRC]].
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==References==
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<ref group="xtra">PMID:19260709</ref><references group="xtra"/>
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<ref group="xtra">PMID: 16439366 </ref><references group="xtra"/>
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<ref group="xtra">PMID: 16306994 </ref><references group="xtra"/>
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<ref group="xtra">PMID: 11329267 </ref><references group="xtra"/>
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<ref group="xtra">PMID: 11006267 </ref><references group="xtra"/>
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<ref group="xtra">PMID: 10460171 </ref><references group="xtra"/>
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<ref group="xtra">PMID: 9405157 </ref><references group="xtra"/>
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<ref group="xtra">PMID: 2115117 </ref><references group="xtra"/>
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<ref group="xtra">PMID: 2420005 </ref><references group="xtra"/>
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<ref group="xtra">PMID: 6299580 </ref><references group="xtra"/>

Revision as of 07:52, 13 June 2012

Proto-oncogene tyrosine-protein kinase Src, 3geq

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Michal Harel, Alexander Berchansky, Joel L. Sussman, Jaime Prilusky

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