Autophosphorylation activates c-Src kinase through global structural rearrangements.

ABSTRACT: The prototypical kinase c-Src plays an important role in numerous signal transduction pathways, where its activity is tightly regulated by two phosphorylation events. Phosphorylation at a specific tyrosine by C-terminal Src kinase inactivates c-Src, whereas autophosphorylation is essential for the c-Src activation process. However, the structural consequences of the autophosphorylation process still remain elusive. Here we investigate how the structural landscape of c-Src is shaped by nucleotide binding and phosphorylation of Tyr⁴¹⁶ using biochemical experiments, hydrogen/deuterium exchange MS, and atomistic molecular simulations. We show that the initial steps of kinase activation involve large rearrangements in domain orientation. The kinase domain is highly dynamic and has st

SUBMITTER: Boczek EE 

PROVIDER: S-EPMC6721954 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature