Dynamics of Hepatitis B Virus Capsid Protein Dimer Regulate Assembly through an Allosteric Network.
Dynamics of Hepatitis B Virus Capsid Protein Dimer Regulate Assembly through an Allosteric Network.
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丙型肝炎病毒衣壳蛋白二聚体的动力学通过变构网络调节组装。
DOI：
10.1021/acschembio.0c00481
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发表时间：
2020-08-21
影响因子：
4
通讯作者：
Bothner B
中科院分区：
文献类型：
--
作者：
Patterson A;Zhao Z;Waymire E;Zlotnick A;Bothner B
虽然有一种有效的疫苗，人类肝炎B病毒（HBV），2.57亿人有慢性感染，没有治愈。病毒衣壳的组装过程是潜在的治疗靶点。为了理解衣壳组装过程，我们研究了衣壳的二聚体构建块。为了了解是什么阻止了组装，我们利用了位于二聚体间界面的组装不合格的突变二聚体Cp 149-Y132 A。该突变导致通过氢氘交换质谱法（HDX-MS）测量的整个二聚体结构的蛋白质动力学变化。为了进一步理解HBV衣壳如何组装，使用了土拨鼠HBV（WHV）衣壳蛋白二聚体（Cp）的同源物。在HDX-MS和天然质谱实验中，WHV比HBV更稳定。由于WHV Cp比HBV更快地组装成病毒衣壳，因此怀疑二聚体内界面和/或接触区域的稳定性增加导致组装速率增加。当比较HBV和人Cp 149-Y132 A时动力学的差异以及当比较HBV和WHV Cps时动力学的差异允许我们绘制HBV二聚体内的变构网络。通过对四种不同衣壳蛋白二聚体的结构、稳定性和动力学的比较，我们得出结论：蛋白亚基动力学调节HBV衣壳组装。
While there is an effective vaccine for Human Hepatitis B Virus (HBV), 257 million people have chronic infections for which there is no cure. The assembly process for the viral capsid is a potential therapeutic target. In order to understand the capsid assembly process, we investigated the dimeric building blocks of the capsid. To understand what blocks assembly, we took advantage of an assembly incompetent mutant dimer, Cp149-Y132A, located in the inter-dimer interface. This mutation leads to changes in protein dynamics throughout the structure of the dimer as measured by hydrogen deuterium exchange mass spectrometry (HDX-MS). To further understand how the HBV capsid assembles, the homolog woodchuck HBV (WHV) capsid protein dimer (Cp) was used. WHV is more stable than HBV in HDX-MS and native mass spectrometry experiments. Because the WHV Cp assembles more rapidly into viral capsids than HBV, it was suspected that an increase in stability of the intra-dimer interface and/or in the contact region leads to increased assembly rates. The differences in dynamics when comparing HBV and human Cp149-Y132A as well as the differences in dynamics when comparing the HBV and WHV Cps allowed us to map an allosteric network within the HBV dimer. Through a careful comparison of structure, stability and dynamics using four different capsid protein dimers, we conclude that protein subunit dynamics regulate HBV capsid assembly.
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