Proto-oncogene tyrosine-protein kinase
From Proteopedia
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. Ref. 1 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. Its subunit structure forms a complex with polyoma virus middle T antigen and interacts with AFAP-110. Interacts with IGF2BP1 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. For details of Proto-oncogene tyrosine-protein kinase SRC see SRC.
3D structures of proto-oncogene tyrosine-protein kinaseUpdated December 2011 Proto-oncogene tyrosine-protein kinase SRC 3lok, 3geq, 2qi8, 3of0 – cNTPK SRC kinase domain (mutant) – chicken 3fj5 - cNTPK SRC SH3 domain Binary complex 1p13 - cNTPK SRC SH2 domain + peptide 1f1w - cNTPK SRC SH2 domain (mutant) + phosphopeptide Proto-oncogene tyrosine-protein kinase LCK 2iim - hNTPK LCK SH3 domain 1kik, 1h92 - hNTPK LCK SH3 domain - NMR Binary complex 1ijr - hNTPK LCK SH2 domain + phosphotyrosine analog 1fbz - hNTPK LCK SH2 domain + inhibitor Proto-oncogene tyrosine-protein kinase FYN 3h0f, 3h0h, 3h0i, 3cqt - hNTPK FYN SH3 domain (mutant) 1zbj - hNTPK FYN SH3 domain – NMR Binary complex 2dq7 - hNTPK FYN kinase domain + antibiotic 1m27 - hNTPK FYN SH3 domain + SH2 domain protein 1A + SLAM Proto-oncogene tyrosine-protein kinase ABL1 3eg0, 3eg2, 3eg3, 3egu - hNTPK ABL1 SH3 domain (mutant) 2fo0 - hNTPK ABL1 SH2]], SH3 domains (mutant) Binary complex 3eg1, 2o88 - hNTPK ABL1 SH3 domain (mutant) + peptide 1ju5 - hNTPK ABL1 SH3 domain + CRK SH2 domain + CRK phosphopeptide - NMR Proto-oncogene tyrosine-protein kinase FER 2kk6 - hNTPK FER SH2 domain Proto-oncogene tyrosine-protein kinase KIT 2ec8 - hNTPK KIT extracellular domain Binary complex 3g0e, 3g0f - hNTPK KIT kinase domain (mutant) + cancer drug 2e9w, 2o26 - hNTPK KIT extracellular domain + stem cell factor Proto-oncogene tyrosine-protein kinase FES 3bkb - hNTPK FES kinase, SH2 domains 2dcr, 1wqu - hNTPK FES SH2 domain – NMR Binary complex 3cd3, 3cbl - hNTPK FES kinase, SH2 domains + peptide Proto-oncogene tyrosine-protein kinase MER 2p0c - hNTPK MER kinase domain 2dbj - hNTPK MER precursor fibronectin domain – NMR Binary complex 3bpr - hNTPK MER kinase domain + inhibitor 3brb - hNTPK MER kinase domain + ADP Proto-oncogene tyrosine-protein kinase YES 2hda - hNTPK YES SH3 domain
References
| |||||||||||
Proteopedia Page Contributors and Editors (what is this?)
Michal Harel, Alexander Berchansky, Joel L. Sussman, Jaime Prilusky
