The RAS-Binding Domain of Human BRAF Protein Serine/Threonine Kinase Exhibits Allosteric Conformational Changes upon Binding HRAS

James M. Aramini, Sergey M. Vorobiev, Lynda M. Tuberty, Haleema Janjua, Elliot T. Campbell, Jayaraman Seetharaman, Min Su, Yuanpeng J. Huang, Thomas B. Acton, Rong Xiao, Liang Tong, Gaetano T. Montelione

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Summary RAS binding is a critical step in the activation of BRAF protein serine/threonine kinase and stimulation of the mitogen-activated protein kinase signaling pathway. Mutations in both RAS and BRAF are associated with many human cancers. Here, we report the solution nuclear magnetic resonance (NMR) and X-ray crystal structures of the RAS-binding domain (RBD) from human BRAF. We further studied the complex between BRAF RBD and the GppNHp bound form of HRAS in solution. Backbone, side-chain, and 19F NMR chemical shift perturbations reveal unexpected changes distal to the RAS-binding face that extend through the core of the RBD structure. Moreover, backbone amide hydrogen/deuterium exchange NMR data demonstrate conformational ensemble changes in the RBD core structure upon complex formation. These changes in BRAF RBD reveal a basis for allosteric regulation of BRAF structure and function, and suggest a mechanism by which RAS binding can signal the drastic domain rearrangements required for activation of BRAF kinase.

Original languageEnglish (US)
Article number3209
Pages (from-to)1382-1393
Number of pages12
JournalStructure
Volume23
Issue number8
DOIs
StatePublished - Aug 7 2015

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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