Structural basis of constitutive c-Src kinase activity due to R175L and W118A mutations.
2021
Cellular Src (c-Src) belongs to a non-receptor membrane-associated tyrosine kinase family that plays essential roles in cellular processes. Growing evidence suggests that R175L and W118A mutations in SH2/SH3 domains of c-Src functionally inactivate these domains leading to constitutive activation of kinase domain (KD). Here we modeled c-SrcR175L, c-SrcW118A and c-SrcW118A+R175L structures by inducing phosphorylation at Y416 or Y527, respectively to characterize the comparative dynamics in the active versus inactive states through molecular dynamics simulation assay. We observed more conformational readjustments in c-Srcopen than its close variants. In particular, C-terminal tail residues of c-SrcW118A-open and c-SrcW118A+R175L-open demonstrate significantly higher transitions. The cross-correlation analysis revealed an anticorrelation behavior in the motion of KD with respect to SH2, SH3 and the linker region of SrcW118A+R175L-open, while in c-SrcWT-open, SH2 and SH3 domains were anticorrelated, while KD and C-terminal tail motions were correlated. Due to these conformational differences, c-Src open forms exhibited lower interaction between pY527 and SH2 domain. Through detailed structural analysis, we observed a uniform myristate binding cavity in c-SrcWT-open, while the myristoyl pockets of mutant forms were deformed. We propose that constitutive activation of mutant Src forms may presumably be achieved by the prolonged membrane binding due to unusual conformations of C-terminal and myristoyl switch residues that may result in a higher dephosphorylation rate at pY527 in the myristoylated c-Src. Thus, our study establishes novel clues to decipher the constitutive activation status of c-Src in response to known mutations that may help in devising novel therapeutic strategies for cancer metastasis treatment.Communicated by Ramaswamy H. Sarma.
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