Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, USA.
Mol Cell Biol. 2014 Mar;34(5):862-76. doi: 10.1128/MCB.01227-13. Epub 2013 Dec 23.
Lipid-anchored Ras GTPases form transient, spatially segregated nanoclusters on the plasma membrane that are essential for high-fidelity signal transmission. The lipid composition of Ras nanoclusters, however, has not previously been investigated. High-resolution spatial mapping shows that different Ras nanoclusters have distinct lipid compositions, indicating that Ras proteins engage in isoform-selective lipid sorting and accounting for different signal outputs from different Ras isoforms. Phosphatidylserine is a common constituent of all Ras nanoclusters but is only an obligate structural component of K-Ras nanoclusters. Segregation of K-Ras and H-Ras into spatially and compositionally distinct lipid assemblies is exquisitely sensitive to plasma membrane phosphatidylserine levels. Phosphatidylserine spatial organization is also modified by Ras nanocluster formation. In consequence, Ras nanoclusters engage in remote lipid-mediated communication, whereby activated H-Ras disrupts the assembly and operation of spatially segregated K-Ras nanoclusters. Computational modeling and experimentation reveal that complex effects of caveolin and cortical actin on Ras nanoclustering are similarly mediated through regulation of phosphatidylserine spatiotemporal dynamics. We conclude that phosphatidylserine maintains the lateral segregation of diverse lipid-based assemblies on the plasma membrane and that lateral connectivity between spatially remote lipid assemblies offers important previously unexplored opportunities for signal integration and signal processing.
脂质锚定的 Ras GTPases 在质膜上形成瞬时的、空间分隔的纳米簇，对于高保真信号传递至关重要。然而，Ras 纳米簇的脂质组成以前尚未被研究过。高分辨率空间映射显示，不同的 Ras 纳米簇具有不同的脂质组成，这表明 Ras 蛋白参与了同种型选择性的脂质分选，并解释了不同 Ras 同种型产生不同信号输出的原因。磷脂酰丝氨酸是所有 Ras 纳米簇的常见成分，但只是 K-Ras 纳米簇的必需结构成分。K-Ras 和 H-Ras 分离成空间和组成上不同的脂质组装体，对质膜磷脂酰丝氨酸水平非常敏感。Ras 纳米簇的形成也会改变磷脂酰丝氨酸的空间组织。因此，Ras 纳米簇进行远程脂质介导的通讯，其中激活的 H-Ras 破坏了空间分隔的 K-Ras 纳米簇的组装和操作。计算建模和实验表明， caveolin 和皮质肌动蛋白对 Ras 纳米簇形成的复杂影响也是通过调节磷脂酰丝氨酸的时空动力学来介导的。我们得出结论，磷脂酰丝氨酸维持了质膜上多种基于脂质的组装体的横向分离，而空间上远程的脂质组装体之间的横向连接为信号整合和信号处理提供了以前未被探索的重要机会。
