Mechanical and kinetic factors drive sorting of F-actin cross-linkers on bundles
Mechanical and kinetic factors drive sorting of F-actin cross-linkers on bundles
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DOI：
10.1073/pnas.1820814116
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发表时间：
2019-08-13
影响因子：
11.1
通讯作者：
Hocky, Glen M.
中科院分区：
文献类型：
--
作者：
Freedman, Simon L.;Suarez, Cristian;Hocky, Glen M.
在细胞中，肌动蛋白结合蛋白（ABP）分类到不同的区域，以建立具有不同功能的F-肌动蛋白网络，包括用于细胞迁移的丝状伪足和细胞分裂所需的收缩环。最近的实验工作揭示了一种基于竞争的机制，可能有助于ABPs的空间定位：短交联蛋白与2条肌动蛋白丝的结合促进了其他短交联蛋白的结合，并抑制了较长交联蛋白的结合（反之亦然）。我们假设这种分类是因为F-肌动蛋白是半柔性的，不能在短距离内弯曲。我们开发了一个数学理论和晶格模型，涵盖了这个过程中最重要的物理参数，并使用粗粒度的模拟与明确的交联剂来表征和测试我们的预测。我们的理论和数据预测的明确依赖于束聚合速率的交联剂分离。我们进行实验，证实这种依赖性，但与一个意外的交叉在一个交联剂在高增长率的优势，其他在缓慢的增长率，我们调查的起源，这种交叉与进一步的模拟。我们描述的非平衡机制可以让细胞组织分子材料来驱动生物过程，我们的研究结果可以指导工程蛋白质材料的交联剂的选择和设计。
In cells, actin-binding proteins (ABPs) sort to different regions to establish F-actin networks with diverse functions, including filopodia used for cell migration and contractile rings required for cell division. Recent experimental work uncovered a competition-based mechanism that may facilitate spatial localization of ABPs: binding of a short cross-linker protein to 2 actin filaments promotes the binding of other short cross-linkers and inhibits the binding of longer cross-linkers (and vice versa). We hypothesize this sorting arises because F-actin is semiflexible and cannot bend over short distances. We develop a mathematical theory and lattice models encompassing the most important physical parameters for this process and use coarse-grained simulations with explicit cross-linkers to characterize and test our predictions. Our theory and data predict an explicit dependence of cross-linker separation on bundle polymerization rate. We perform experiments that confirm this dependence, but with an unexpected cross-over in dominance of one cross-linker at high growth rates to the other at slow growth rates, and we investigate the origin of this cross-over with further simulations. The nonequilibrium mechanism that we describe can allow cells to organize molecular material to drive biological processes, and our results can guide the choice and design of cross-linkers for engineered protein-based materials.