The Journal of Membrane Biology ( IF 2.3 ) Pub Date : 2021-04-07 , DOI: 10.1007/s00232-021-00176-z Cesar A López 1 , Animesh Agarwal 1 , Que N Van 2 , Andrew G Stephen 2 , S Gnanakaran 1
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Small GTPase proteins are ubiquitous and responsible for regulating several processes related to cell growth and differentiation. Mutations that stabilize their active state can lead to uncontrolled cell proliferation and cancer. Although these proteins are well characterized at the cellular scale, the molecular mechanisms governing their functions are still poorly understood. In addition, there is limited information about the regulatory function of the cell membrane which supports their activity. Thus, we have studied the dynamics and conformations of the farnesylated KRAS4b in various membrane model systems, ranging from binary fluid mixtures to heterogeneous raft mimics. Our approach combines long time-scale coarse-grained (CG) simulations and Markov state models to dissect the membrane-supported dynamics of KRAS4b. Our simulations reveal that protein dynamics is mainly modulated by the presence of anionic lipids and to some extent by the nucleotide state (activation) of the protein. In addition, our results suggest that both the farnesyl and the polybasic hypervariable region (HVR) are responsible for its preferential partitioning within the liquid-disordered (Ld) domains in membranes, potentially enhancing the formation of membrane-driven signaling platforms.
Graphic Abstract
中文翻译：
揭示 KRAS4b 在脂质模型膜上的动力学
小 GTPase 蛋白无处不在，负责调节与细胞生长和分化相关的几个过程。稳定其活跃状态的突变可导致不受控制的细胞增殖和癌症。尽管这些蛋白质在细胞尺度上得到了很好的表征，但对其功能的分子机制仍然知之甚少。此外，关于支持其活性的细胞膜的调节功能的信息有限。因此，我们研究了各种膜模型系统中法尼基化 KRAS4b 的动力学和构象，范围从二元流体混合物到异质筏模拟物。我们的方法结合了长时间尺度的粗粒度 (CG) 模拟和马尔可夫状态模型来剖析 KRAS4b 的膜支持动力学。我们的模拟表明，蛋白质动力学主要受阴离子脂质的存在以及在某种程度上受蛋白质的核苷酸状态（激活）的调节。此外，我们的研究结果表明，法呢基和多元高变区（HVR）都负责其在膜中液体无序（Ld）结构域内的优先分配，从而可能增强膜驱动信号平台的形成。
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