Li Zhen-Lu, Buck Matthias
Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Department of Neurosciences, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Department of Pharmacology, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Center for Proteomics and Bioinformatics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Structure. 2017 Apr 4;25(4):679-689.e2. doi: 10.1016/j.str.2017.02.007. Epub 2017 Mar 9.
The structural, dynamical, and functional characterization of the small GTPase K-Ras has become a research area of intense focus due to its high occurrence in human cancers. Ras proteins are only fully functional when they interact with the plasma membrane. Here we present all-atom molecular dynamics simulations (totaling 5.8 μs) to investigate the K-Ras4A protein at membranes that contain anionic lipids (phosphatidyl serine or phosphatidylinositol bisphosphate). We find that similarly to the homologous and highly studied K-Ras4B, K-Ras4A prefers a few distinct orientations at the membrane. Remarkably, the protein surface charge and certain lipids can strongly modulate the orientation preference. In a novel analysis, we reveal that the electrostatic interaction (attraction but also repulsion) between the protein's charged residues and anionic lipids determines the K-Ras4A orientation, but that this is also influenced by the topology of the protein, reflecting the geometry of its surfaces.
由于小GTP酶K-Ras在人类癌症中高发，其结构、动力学和功能特性已成为一个备受关注的研究领域。Ras蛋白只有在与质膜相互作用时才具有完全功能。在此，我们展示了全原子分子动力学模拟（总计5.8微秒），以研究K-Ras4A蛋白在含有阴离子脂质（磷脂酰丝氨酸或磷脂酰肌醇二磷酸）的膜上的情况。我们发现，与同源且研究深入的K-Ras4B类似，K-Ras4A在膜上倾向于几个不同的方向。值得注意的是，蛋白质表面电荷和某些脂质可以强烈调节方向偏好。在一项新颖的分析中，我们揭示了蛋白质带电残基与阴离子脂质之间的静电相互作用（包括吸引和排斥）决定了K-Ras4A的方向，但这也受到蛋白质拓扑结构的影响，反映了其表面的几何形状。
