Elucidating structural details of ras-effector interactions

Abstract

Small membrane-associated Ras proteins mediate a wide range of cellular functions, such as cell proliferation, migration, survival, and differentiation; through binding and activating numerous effectors. Constitutively active mutant Ras proteins are detected in various types of human cancer and Ras community seeks approaches other than small-molecule Ras inhibitors; such as targeting the protein-protein interactions in the downstream Ras effector pathways and preventing its membrane localization. Although the most studied effectors of Ras, i.e. Raf, PI3K and RalGDS, bind Ras through the same site, they elicit opposing signaling pathways and thus, the temporal and spatial decision of the cell among them is critical. Elucidating the structural details of Ras-effector interactions can help us understand the cell decision and target the protein-protein interactions precisely. However, only a few crystal structures of Ras in complex with an effector are deposited in PDB. Here, the 3D structures of Ras/effector complexes were modeled with the PRISM algorithm and important binding sites as well as hot spot residues on Ras were identified. The effectors were also classified according to the binding regions on Ras, to determine the competitive pathways and the binding regions other than the “effector lobe”. The modeled complexes reveal important information about the interfaces between Ras and its partners with the potential of guiding drug design studies to block oncogenic Ras signaling.