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Mechanism of actin filament nucleation
Biophysical Journal ( IF 3.2 ) Pub Date : 2021-09-10 , DOI: 10.1016/j.bpj.2021.09.006
Aaron D Rosenbloom 1 , Elizabeth W Kovar 2 , David R Kovar 3 , Leslie M Loew 4 , Thomas D Pollard 5
Affiliation  

We used computational methods to analyze the mechanism of actin filament nucleation. We assumed a pathway where monomers form dimers, trimers, and tetramers that then elongate to form filaments but also considered other pathways. We aimed to identify the rate constants for these reactions that best fit experimental measurements of polymerization time courses. The analysis showed that the formation of dimers and trimers is unfavorable because the association reactions are orders of magnitude slower than estimated in previous work rather than because of rapid dissociation of dimers and trimers. The 95% confidence intervals calculated for the four rate constants spanned no more than one order of magnitude. Slow nucleation reactions are consistent with published high-resolution structures of actin filaments and molecular dynamics simulations of filament ends. One explanation for slow dimer formation, which we support with computational analysis, is that actin monomers are in a conformational equilibrium with a dominant conformation that cannot participate in the nucleation steps.



中文翻译:

肌动蛋白丝成核机制

我们使用计算方法来分析肌动蛋白丝成核的机制。我们假设了一种途径,其中单体形成二聚体、三聚体和四聚体,然后伸长形成细丝,但也考虑了其他途径。我们旨在确定最适合聚合时间过程的实验测量的这些反应的速率常数。分析表明,二聚体和三聚体的形成是不利的,因为缔合反应比以前工作中估计的慢几个数量级,而不是因为二聚体和三聚体的快速解离。为四个速率常数计算的 95% 置信区间不超过一个数量级。缓慢的成核反应与已发表的肌动蛋白丝的高分辨率结构和丝末端的分子动力学模拟一致。我们通过计算分析支持缓慢二聚体形成的一种解释是,肌动蛋白单体处于构象平衡,具有不能参与成核步骤的主要构象。

更新日期:2021-10-19
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