Abstract
Abstract RASSF5 is a tumor suppressor, which acts as an adaptor linking Ras and the Hippo pathways. RASSF5 activates MST1/2, a key upstream protein of the Hippo pathway, through SARAH domain heterodimerization, resulting in Hippo signaling. Signaling stimulates YAP1 phosphorylation, leading to its degradation and thereby cell apoptosis. Association with K-Ras4B promotes RASSF5 to release its SARAH which heterodimerizes with MST1/2. We aim to reveal how K-Ras4B regulates the Hippo pathway through RASSF5 by resolving the structure and conformational dynamics of RASSF5 complexes. Our modeling and simulations help elucidate the intrinsic dynamic interactions of RASSF5 RA (Ras binding) and SARAH domains. Surprisingly, we found that the residue E388 on RASSF5 SARAH plays a significant role in the dynamic mechanism of SARAH homo-/hetero- dimerization and the RA-SARAH association. The mutants E388A and E388K dramatically decrease the strength of RASSF5 homo-SARAH and RASSF5-MST2 hetero-SARAH, suggesting that the E388 mutation may be oncogenic. Simulations of selected RASSF5 configurations with GTP-bound K-Ras4B indicate that the interactions between RA and SARAH are reduced. We conclude that Ras binding weakens the RA-SARAH association, increasing the SARAH dynamic fluctuation. The released RASSF5 SARAH has high propensity to dimerize with MST1/2 SARAH, activating Hippo signaling thus cancer suppression. Funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, NIH under contract HHSN261200800001E. Citation Format: Tsung-Jen Liao, Hyunbum Jang, Chung-Jung Tsai, David Fushman, Ruth Nussinov. The dynamic mechanism of SARAH domain in RASSF5 activation by K-Ras4B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1367. doi:10.1158/1538-7445.AM2017-1367
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