Ras Nanoclusters and Membrane Domains

Abstract

Lipid-anchored signaling proteins assemble into dynamic signaling platforms on the plasma membrane [1] as well as in model membranes [2]. One of the best characterized examples of these membrane-assemblies are those of Ras proteins. Ras is a molecular switch that controls cell growth and proliferation. The primary site of Ras action is the inner surface of the plasma. A fraction of membrane-associated Ras proteins forms small transient preotlipid assemblies, or nanoclusters, that are the exclusive sites of effector recruitment and activation. Therefore, nanoclusters represent novel therapeutic targets to prevent defective Ras signaling, a common cause of many cancers. However, due to the dynamic nature of nanoclusters, with critical events occurring on nano- to micro-second time scales, major questions are difficult to address using current experimental approaches. For instance, it is unclear why highly homologous Ras isoforms form different clusters and whether nanoclusters sense/stabilize curved membrane regions or facilitate membrane deformation. We have begun to address these questions based on coarse-grained molecular simulations [3,4]. This presentation will focus on the role of cholesterol and protein concentration on Ras clustering and the effect of the clusters on the mechanical properties of the host membrane. [1] Plowman, S. J.; Muncke, C.; Parton, R. G.; Hancock, J. F. Proc Natl Acad Sci U S A 2005, 102, 15500-5. [2] Weise, K.; Kapoor, S.; Denter, C.; Nikolaus, J.; Opitz, N.; Koch, S.; Triola, G.; Herrmann, A.; Waldmann, H.; Winter, R. J Am Chem Soc 2011, 133, 880-7. [3] Janosi, L.; Li, Z.; Hancock, J. F.; Gorfe, A. A. Proc Natl Acad Sci USA 2012, 109, 8097-102. [4] Li, Z.; Janosi, L.; Gorfe, A. A. J Am Chem Soc 2012, In press.