Three-Dimensional Structures of Soluble CD4-Bound States of Trimeric Simian Immunodeficiency Virus Envelope Glycoproteins Determined by Using Cryo-Electron Tomography
Three-Dimensional Structures of Soluble CD4-Bound States of Trimeric Simian Immunodeficiency Virus Envelope Glycoproteins Determined by Using Cryo-Electron Tomography
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DOI：
10.1128/jvi.05297-11
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发表时间：
2011-12-01
影响因子：
5.4
通讯作者：
Subramaniam, Sriram
中科院分区：
文献类型：
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作者：
White, Tommi A.;Bartesaghi, Alberto;Subramaniam, Sriram
猴免疫缺陷病毒(SIV)和人类免疫缺陷病毒1型(HIV-1)病毒粒子表面的三聚体包膜糖蛋白(Env)尖峰由病毒糖蛋白gp120和gp41的三个异源二聚体组成。虽然已知gp120与细胞表面的CD4和趋化因子受体结合可以引起gp120和gp41的构象变化，但直到最近才阐明了三聚体的四级结构的变化。对于HIV-1bal分离株，CD4附着导致三聚体从“闭合”构象到“开放”构象的惊人重排。然而，CD4对SIV三聚体的影响还没有被描述。利用冷冻电子断层扫描技术，我们现在已经确定了三种不同菌株(SIVmneE11S、SIVmac239和SIV CP-MAC)SIV环境三聚体的可溶性CD4(SCD4)结合态的分子结构。与HIV-1bal相比，SIVmneE11S和SIVmac239Env在sCD4结合后仅表现出轻微的构象变化。在SIV CP-MAC中，三聚体Env显示出与HIV-1 Bal Env在sCD4-Complex状态下类似的结构性“开放”构象，我们表明，sCD4或7D3抗体结合后，构象没有明显的进一步变化。密度图还显示，7D3和17b抗体针对gp120上的表位，这些表位位于辅助受体结合部位的相反一侧。这些结果为了解SIV Env的结构多样性提供了新的见解，并表明与三聚体SIV Env结合的sCD4的取向存在依赖于应变的变化。
The trimeric envelope glycoprotein (Env) spikes displayed on the surfaces of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) virions are composed of three heterodimers of the viral glycoproteins gp120 and gp41. Although binding of gp120 to cell surface CD4 and a chemokine receptor is known to elicit conformational changes in gp120 and gp41, changes in quaternary structure of the trimer have only recently been elucidated. For the HIV-1 BaL isolate, CD4 attachment results in a striking rearrangement of the trimer from a "closed" to an "open" conformation. The effect of CD4 on SIV trimers, however, has not been described. Using cryo-electron tomography, we have now determined molecular architectures of the soluble CD4 (sCD4)-bound states of SIV Env trimers for three different strains (SIVmneE11S, SIVmac239, and SIV CP-MAC). In marked contrast to HIV-1 BaL, SIVmneE11S and SIVmac239 Env showed only minor conformational changes following sCD4 binding. In SIV CP-MAC, where trimeric Env displays a constitutively "open" conformation similar to that seen for HIV-1 BaL Env in the sCD4-complexed state, we show that there are no significant further changes in conformation upon the binding of either sCD4 or 7D3 antibody. The density maps also show that 7D3 and 17b antibodies target epitopes on gp120 that are on opposites sides of the coreceptor binding site. These results provide new insights into the structural diversity of SIV Env and show that there are strain-dependent variations in the orientation of sCD4 bound to trimeric SIV Env.