He Xuan, Du Kui, Wang Yuanhao, Fan Jigang, Li Mingyu, Ni Duan, Lu Shaoyong, Bian Xiaolan, Liu Yaqin
Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, China.
Front Mol Biosci. 2022 Apr 8;9:860962. doi: 10.3389/fmolb.2022.860962. eCollection 2022.
The Ras-specific guanine nucleotide exchange factors Son of Sevenless (SOS) regulates Ras activation by converting inactive GDP-bound to active GTP-bound states. The catalytic activity of Ras is further allosterically regulated by GTP-Ras bound to a distal site through a positive feedback loop. To address the mechanism underlying the long-range allosteric activation of the catalytic K-Ras4B by an additional allosteric GTP-Ras through SOS, we employed molecular dynamics simulation of the K-Ras4B•SOS complex with and without an allosteric GTP-bound K-Ras4B. We found that the binding of an allosteric GTP-K-Ras4B enhanced the affinity between the catalytic K-Ras4B and SOS, forming a more stable conformational state. The peeling away of the switch I from the nucleotide binding site facilitated the dissociation of GDP, thereby contributing to the increased nucleotide exchange rate. The community networks further showed stronger edge connection upon allosteric GTP-K-Ras4B binding, which represented an increased interaction between catalytic K-Ras4B and SOS. Moreover, GTP-K-Ras4B binding transmitted allosteric signaling pathways though the Cdc25 domain of SOS that enhanced the allosteric regulatory from the K-Ras4B allosteric site to the catalytic site. This study may provide an in-depth mechanism for abnormal activation and allosteric regulation of K-Ras4B.
Ras特异性鸟嘌呤核苷酸交换因子七号less之子（SOS）通过将无活性的GDP结合态转变为活性的GTP结合态来调节Ras激活。Ras的催化活性通过与远端位点结合的GTP-Ras形成的正反馈环进一步受到变构调节。为了探究通过SOS由另一个变构GTP-Ras对催化性K-Ras4B进行远程变构激活的潜在机制，我们对有和没有变构GTP结合的K-Ras4B的K-Ras4B•SOS复合物进行了分子动力学模拟。我们发现变构GTP-K-Ras4B的结合增强了催化性K-Ras4B与SOS之间的亲和力，形成了更稳定的构象状态。开关I从核苷酸结合位点的剥离促进了GDP的解离，从而导致核苷酸交换速率增加。群落网络在变构GTP-K-Ras4B结合后进一步显示出更强的边连接，这代表了催化性K-Ras4B与SOS之间增加的相互作用。此外，GTP-K-Ras4B的结合通过SOS的Cdc25结构域传递变构信号通路，增强了从K-Ras4B变构位点到催化位点的变构调节。这项研究可能为K-Ras4B的异常激活和变构调节提供深入的机制。
