Structure
Volume 23, Issue 3, 3 March 2015, Pages 505-516
Journal home page for Structure

Article
Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD

https://doi.org/10.1016/j.str.2014.12.017Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Crystal structures of HRas and HRasQ61L have been solved in complex with Raf-RBD

  • The Q61L mutation has global effects on Ras and Raf-RBD in the complex

  • The Q61L mutation changes flexibility at interface linking to Raf-RBD loop L4

  • Ras mutants can contribute to oncogenesis beyond local effects on the active site

Summary

The Ras/Raf/MEK/ERK signal transduction pathway is a major regulator of cell proliferation activated by Ras-guanosine triphosphate (GTP). The oncogenic mutant RasQ61L is not able to hydrolyze GTP in the presence of Raf and thus is a constitutive activator of this mitogenic pathway. The Ras/Raf interaction is essential for the activation of the Raf kinase domain through a currently unknown mechanism. We present the crystal structures of the Ras-GppNHp/Raf-RBD and RasQ61L-GppNHp/Raf-RBD complexes, which, in combination with MD simulations, reveal differences in allosteric interactions leading from the Ras/Raf interface to the Ras calcium-binding site and to the remote Raf-RBD loop L4. In the presence of Raf, the RasQ61L mutant has a rigid switch II relative to the wild-type and increased flexibility at the interface with switch I, which propagates across Raf-RBD. We show that in addition to local perturbations on Ras, RasQ61L has substantial long-range effects on the Ras allosteric lobe and on Raf-RBD.

Cited by (0)