Conformation of the GTPase Ras in the Membrane Affects Nanoscale Clustering and Raf Kinase Recruitment♦
The Efficacy of Raf Kinase Recruitment to the GTPase H-ras Depends on H-ras Membrane Conformer-specific Nanoclustering
♦ See referenced article, J. Biol. Chem. 2014, 289, 9519–9533
Ras proteins are critical modulators of the important Ras-MAPK signaling pathway. Much is known about the solution structures and biochemistry of Ras proteins. However, their organization in a lipid membrane is not as well understood, although it is recognized that it has a significant impact on their activity. In this Paper of the Week, a team led by Daniel Abankwa at the Åbo Akademi University in Finland used fluorescence imaging methods in mammalian cells and mathematical modeling to investigate the coupling between the conformation of a Ras protein (H-ras) and its organization into signaling packages called nanoclusters. The investigators found that specific mutations that affect the conformation of H-ras on the membrane also affect the stability of the nanocluster. Stable nanoclusters recruited the effector kinase Raf to Ras on the membrane more effectively, directly impacting the rest of the Ras-MAPK pathway. “Our results show that mutations in Ras can affect its nanoclustering response and thus allosterically effector recruitment and downstream signaling,” comment the authors. “We postulate that cancer- and developmental disease-linked mutations that are associated with the Ras membrane conformation may exhibit so far unrecognized Ras nanoclustering and therefore signaling alterations.”
Structures of c-Raf (green) bound to the computationally generated models of membrane-bound H-ras (blue) in the GDP (left) and GTP (right) conformations.
- © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
