Hassinger Julian E, Oster George, Drubin David G, Rangamani Padmini
Biophysics Graduate Group, University of California, Berkeley, CA 94720.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1118-E1127. doi: 10.1073/pnas.1617705114. Epub 2017 Jan 26.
A critical step in cellular-trafficking pathways is the budding of membranes by protein coats, which recent experiments have demonstrated can be inhibited by elevated membrane tension. The robustness of processes like clathrin-mediated endocytosis (CME) across a diverse range of organisms and mechanical environments suggests that the protein machinery in this process has evolved to take advantage of some set of physical design principles to ensure robust vesiculation against opposing forces like membrane tension. Using a theoretical model for membrane mechanics and membrane protein interaction, we have systematically investigated the influence of membrane rigidity, curvature induced by the protein coat, area covered by the protein coat, membrane tension, and force from actin polymerization on bud formation. Under low tension, the membrane smoothly evolves from a flat to budded morphology as the coat area or spontaneous curvature increases, whereas the membrane remains essentially flat at high tensions. At intermediate, physiologically relevant, tensions, the membrane undergoes a "snap-through instability" in which small changes in the coat area, spontaneous curvature or membrane tension cause the membrane to "snap" from an open, U-shape to a closed bud. This instability can be smoothed out by increasing the bending rigidity of the coat, allowing for successful budding at higher membrane tensions. Additionally, applied force from actin polymerization can bypass the instability by inducing a smooth transition from an open to a closed bud. Finally, a combination of increased coat rigidity and force from actin polymerization enables robust vesiculation even at high membrane tensions.
细胞运输途径中的一个关键步骤是由蛋白质衣被介导的膜出芽，最近的实验表明，膜张力升高可抑制这一过程。网格蛋白介导的内吞作用（CME）等过程在各种生物体和机械环境中都具有稳健性，这表明该过程中的蛋白质机制已经进化，以利用某些物理设计原则，确保在诸如膜张力等相反力的作用下实现稳健的囊泡化。我们使用膜力学和膜蛋白相互作用的理论模型，系统地研究了膜刚性、蛋白质衣被诱导的曲率、蛋白质衣被覆盖的面积、膜张力以及肌动蛋白聚合产生的力对芽形成的影响。在低张力下，随着衣被面积或自发曲率的增加，膜从平坦形态平滑地演变为芽状形态，而在高张力下，膜基本上保持平坦。在中等的、生理相关的张力下，膜会经历“突变不稳定性”，其中衣被面积、自发曲率或膜张力的微小变化会导致膜从开放的U形“突变”为封闭的芽。通过增加衣被的弯曲刚性，可以消除这种不稳定性，从而在更高的膜张力下实现成功出芽。此外，肌动蛋白聚合产生的作用力可以通过诱导从开放芽到封闭芽的平滑转变来绕过这种不稳定性。最后，增加衣被刚性和肌动蛋白聚合产生的力相结合，即使在高膜张力下也能实现稳健的囊泡化。
