Immature HIV-1 assembles from Gag dimers leaving partial hexamers at lattice edges as potential substrates for proteolytic maturation.
Immature HIV-1 assembles from Gag dimers leaving partial hexamers at lattice edges as potential substrates for proteolytic maturation.
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DOI：
10.1073/pnas.2020054118
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发表时间：
2021-01-19
影响因子：
11.1
通讯作者：
Briggs JAG
中科院分区：
文献类型：
--
作者：
Tan A;Pak AJ;Morado DR;Voth GA;Briggs JAG
HIV - 1病毒粒子的组装由病毒Gag蛋白驱动，该蛋白在病毒包膜内表面寡聚形成六聚体阵列，形成一个包含大小间隙的截短球形晶格。然后Gag被病毒蛋白酶切割，解聚并重新排列以形成成熟的、具有传染性的病毒。在此，我们展示了未成熟Gag晶格边缘的结构以及分子动力学模拟结果。我们的分析表明，Gag二聚体是HIV - 1病毒粒子的基本组装单位，晶格边缘是部分六聚体，并且部分六聚体易于发生结构变化从而使蛋白酶能够切割Gag。这些发现为未成熟病毒的组装、其结构以及在成熟过程中如何解聚提供了见解。
未成熟HIV - 1 Gag的CA（衣壳）结构域以及相邻的间隔肽1（SP1）通过形成CA六聚体晶格在病毒组装中起关键作用，该晶格通过在出芽部位包含小的晶格缺陷和一个大的间隙来适应病毒包膜的曲率。这个晶格通过六聚体内部以及六聚体之间的CA - CA相互作用而稳定，这在调节病毒组装和成熟方面很重要。我们应用子断层平均和分类方法来确定晶格边缘处CA的寡聚化状态，并发现CA形成部分六聚体。这些结构揭示了晶格边缘处由CA - SP1形成的相互作用网络。我们还对稳定未成熟晶格和部分CA - SP1螺旋束的CA - CA相互作用进行了原子分子动力学模拟。自由能计算表明，与完整的六螺旋束相比，部分六聚体中螺旋 - 卷曲转变的倾向增加。综上所述，这些结果表明CA二聚体是晶格组装的基本单位，部分六聚体存在于晶格边缘，它们处于螺旋 - 卷曲动态平衡中，并且部分螺旋束更有可能展开，代表着HIV - 1成熟起始的潜在位点。
HIV-1 particle assembly is driven by the viral Gag protein, which oligomerizes into a hexameric array on the inner surface of the viral envelope, forming a truncated spherical lattice containing large and small gaps. Gag is then cut by the viral protease, disassembles, and rearranges to form the mature, infectious virus. Here, we present structures and molecular dynamics simulations of the edges of the immature Gag lattice. Our analysis shows that Gag dimers are the basic assembly unit of the HIV-1 particle, lattice edges are partial hexamers, and partial hexamers are prone to structural changes allowing protease to cut Gag. These findings provide insights into assembly of the immature virus, its structure, and how it disassembles during maturation. The CA (capsid) domain of immature HIV-1 Gag and the adjacent spacer peptide 1 (SP1) play a key role in viral assembly by forming a lattice of CA hexamers, which adapts to viral envelope curvature by incorporating small lattice defects and a large gap at the site of budding. This lattice is stabilized by intrahexameric and interhexameric CA-CA interactions, which are important in regulating viral assembly and maturation. We applied subtomogram averaging and classification to determine the oligomerization state of CA at lattice edges and found that CA forms partial hexamers. These structures reveal the network of interactions formed by CA-SP1 at the lattice edge. We also performed atomistic molecular dynamics simulations of CA-CA interactions stabilizing the immature lattice and partial CA-SP1 helical bundles. Free energy calculations reveal increased propensity for helix-to-coil transitions in partial hexamers compared to complete six-helix bundles. Taken together, these results suggest that the CA dimer is the basic unit of lattice assembly, partial hexamers exist at lattice edges, these are in a helix-coil dynamic equilibrium, and partial helical bundles are more likely to unfold, representing potential sites for HIV-1 maturation initiation.
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