Identification of the HIV-1 Vif and Human APOBEC3G Protein Interface.
Identification of the HIV-1 Vif and Human APOBEC3G Protein Interface.
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DOI：
10.1016/j.celrep.2015.10.068
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发表时间：
2015-12-01
期刊：
影响因子：
8.8
通讯作者：
Ooms M
中科院分区：
文献类型：
--
作者：
Letko M;Booiman T;Kootstra N;Simon V;Ooms M
人类细胞表达天然的抗病毒蛋白，如APOBEC 3G（A3 G），有效地限制HIV复制。作为反防御，HIV编码辅助蛋白Vif，其结合A3 G并介导其蛋白酶体降解。我们对Vif和A3 G如何相互作用的结构知识非常有限，因为没有共同结构。我们通过使用全长A3 G，患者衍生的Vif变体和HIV强制进化的功能测定，确定了Vif和A3 G之间的特定接触点。这些锚点被用于建模和验证Vif-A3 G接口。共结构模型表明，β4-α4 A3 G环是Vif的核心结合位点，与Vif的正电荷口袋形成广泛的相互作用。我们的数据提供了这种病毒-宿主界面的功能图，并为通过阻断Vif-A3 G相互作用来阻断HIV复制的靶向方法开辟了新的途径。
Human cells express natural antiviral proteins, such as APOBEC3G (A3G) that potently restrict HIV replication. As a counter defense, HIV encodes the accessory protein Vif, which binds A3G and mediates its proteasomal degradation. Our structural knowledge on how Vif and A3G interact is very limited since a co-structure is not available. We identified specific points of contact between Vif and A3G by using functional assays with full-length A3G, patient-derived Vif variants and HIV forced evolution. These anchor points were used to model and validate the Vif-A3G interface. The resultant co-structure model shows that the negatively charged β4-α4 A3G loop, which contains primate-specific variation, is the core Vif binding site and forms extensive interactions with a positively charged pocket in HIV Vif. Our data present a functional map of this viral-host interface and opens new avenues for targeted approaches to block HIV replication by obstructing the Vif-A3G interaction.