The role of the linker between the SH2 domain and catalytic domain in the regulation and function of Src

摘要: The crystal structures of the regulated Src and Hck tyrosine kinases show intramolecular interactions between phosphorylated tail SH2 domain as well SH3 domain, SH2-catalytic linker (SH2-CD linker) catalytic domain. relative contribution these to regulation activity is poorly understood. Mutational analysis Lck revealed that interaction SH2-CD with crucial for regulation. Moreover, three sites one at beginning (Trp260) two back small lobe, opposite cleft (beta2/beta3 loop; alphaC/beta4 loop), impinge on activity. Other activating mutations map front in loop preceding alphaC-helix (beta3/alphaC loop). mutants are deregulated mammalian cells but transform fibroblasts weakly, suggesting may bind cellular components. Interpretation our results basis structure favours a model which correctly positioned exerts an inhibitory function catalysis family members by facilitating displacement alphaC-helix. This study provide template generation versions other protein kinases.