Microtubule Severing Enzymes Oligomerization and Allostery: A Tale of Two Domains
Microtubule Severing Enzymes Oligomerization and Allostery: A Tale of Two Domains
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微管切断酶寡聚化和变构：两个域的故事
DOI：
10.1021/acs.jpcb.2c05288
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Dima, Ruxandra I.
中科院分区：
文献类型：
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作者：
Macke, Amanda C.;Kelly, Maria S.;Varikoti, Rohith Anand;Mullen, Sarah;Groves, Daniel;Forbes, Clare;Dima, Ruxandra I.
切断蛋白是来自 AAA+（与各种细胞活动相关的 ATP 酶）超家族的纳米机器，其功能是重塑最大的细胞丝、微管。出于功能原因，标准 AAA+ 机器采用六聚环结构，而在没有核苷酸的情况下主要是单体。据信，两种主要的切割蛋白，剑蛋白和 spastin，都遵循这一趋势。然而，研究表明它们在功能相关的辅助因子存在下填充低阶寡聚体。我们的模拟表明，首选的寡聚体组装取决于结合配偶体和切断蛋白的类型。基本动力学分析预测寡聚物的稳定性取决于单体的螺旋束结构域 (HBD) 和相邻单体的核苷酸结合结构域 (NBD) 的凸面之间的界面强度。热点分析发现，由 HBD 尖端和 C 端 (CT) 螺旋组成的区域是响应核苷酸、底物和单体间结合的变构网络之间唯一的共同元素。聚类分析表明，单体中 HBD 尖端的二级结构与其低聚物中所采用的结构之间的转变存在多种途径。
Severing proteins are nanomachines from the AAA+ (ATPases associated with various cellular activities) superfamily whose function is to remodel the largest cellular filaments, microtubules. The standard AAA+ machines adopt hexameric ring structures for functional reasons, while being primarily monomeric in the absence of the nucleotide. Both major severing proteins, katanin and spastin, are believed to follow this trend. However, studies proposed that they populate lower-order oligomers in the presence of cofactors, which are functionally relevant. Our simulations show that the preferred oligomeric assembly is dependent on the binding partners and on the type of severing protein. Essential dynamics analysis predicts that the stability of an oligomer is dependent on the strength of the interface between the helical bundle domain (HBD) of a monomer and the convex face of the nucleotide binding domain (NBD) of a neighboring monomer. Hot spots analysis found that the region consisting of the HBD tip and the C-terminal (CT) helix is the only common element between the allosteric networks responding to nucleotide, substrate, and intermonomer binding. Clustering analysis indicates the existence of multiple pathways for the transition between the secondary structure of the HBD tip in monomers and the structure(s) it adopts in oligomers.