Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II

63-POS Board 16 Identification of Effector Binding Sites on H-Ras Explains Signal Propagation Serena Muratcioglu 1 , Attila Gursoy 1 , Ozlem Keskin 1 , Ruth Nussinov 2 . 1 Koc University, Istanbul, Turkey, 2 NCI Frederick, Frederick, MD, USA. Ras proteins (HRAS, NRAS and KRAS) are small GTPases that regulate diverse cellular processes. These proteins activate multiple signaling pathways with complex and divergent effects including cell cycle progression, cell differentiation and survival. Ras proteins cycle between two conformations: GDP-bound inactive and GTP-bound active forms. Active Ras proteins transmit the information through a physical interaction with its downstream effector proteins. Therefore, it is of capital importance to determine the complex structures of ras with these proteins to understand the pathways at the structural level. Here we show that Ras-GTP interacts with its downstream effector proteins through different interfaces. These interface regions include Switch I effector binding site and allosteric site. The predominant interface region consists of α1, β2, β3, β4 and β5.The effector proteins that bind to these regions are Raf-1, B-raf, PI3Kγ, PLCε, and Byr2 (crystal structures of the complexes are available), Cdc42, Ftase (the complexes are predicted) and RASSF1 (structure modeled and interface predicted). The second interface region populated by RAIN, RGS12, RGL1 (structure modeled and interface predicted) and TIAM proteins (the complexes are predicted) includes α2, α 3, β7, α4, β10 and α5. Few effector proteins such as AFAD, RIN1 and FAK bind to H-Ras through an interface region that partially overlaps both binding sites. Here we also identify mutually inclusive/exclusive interactions by predicting and comparing the interface regions of H-Ras with its partners. This may help us identify the pathways that can be activated simultaneously by active Ras proteins.

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