Dynamics of Hepatitis B virus capsid protein dimer regulate assembly through an allosteric network
Angela Patterson, Zhongchao Zhao, Elizabeth Waymire, Adam Zlotnick, Brian Bothner
PMID: 32662972 DOI: 10.1021/acschembio.0c00481
Abstract
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. 作者: StephenW 时间: 2020-7-15 11:33