Son of sevenless homology 1 (SOS1) is a robust guanine nucleotide exchange factor (GEF) that exchanges GDP by GTP and activates Ras. SOS1 is a large multidomain protein with molecular weight of ~153 kDa. The C-terminal catalytic region, composed of RAS exchanger motif (REM) and CDC25 domains, is responsible for Ras activation. SOS1 offers two Ras binding sites; one at the allosteric site in REM and the other at the catalytic site in CDC25. Experimental studies provided a Ras-SOS1-Ras ternary complex and suggested that Ras binding to REM allosteric site is essential to activate GDP-bound Ras at the CDC25 catalytic site. However, details of SOS1 conformational changes due to different binding modes of Ras at the allosteric and catalytic sites in Ras activation are not well understood. Here, using molecular dynamics (MD) simulations, we examine Ras activation mechanism for SOS1 systems containing GDP- and GTP-bound, and nucleotide-free KRas4B. Among the three Ras isoforms, including HRas, NRas, and KRas (with two splice variants of KRas4A and KRas4B), KRas4B is highly oncogenic, the most frequently mutated in RAS-driven cancers. We observed that the REM domain inherently and sterically obstructs the Ras binding site of CDC25 domain. Upon binding to the REM allosteric site, KRas4B-GTP relieves the steric occlusion, making the CDC25 catalytic site capable of associating with KRas4B-GDP, leading to the nucleotide exchange. Allosteric effects lead to the dislocation of the helix-hairpin motif at the CDC25 catalytic site. This large movement of the helix-hairpin motif causes the Ras catalytic site to open and liberates GDP. Allosteric signals propagating through the REM-CDC25 tandem domains of SOS1 can explain the communication between two Ras proteins modulating the large conformational changes. Our simulations provide insight into the structural correlation of KRas4B-SOS1 as well as the allosteric effect. The conformational changes of SOS1 correspond to the allosteric signaling between two KRas4B at REM and CDC25 domains, promoting Ras activation.

Citation Format: Tsung-Jen Liao, Hyunbum Jang, David Fushman, Ruth Nussinov. SOS1 allosterically linked conformational changes modulate KRas4B activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 683.