117
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.
