Identification and characterization of loop7 motif and its role in regulating biological function of human APOBEC3G through molecular modeling and biological assay.
Identification and characterization of loop7 motif and its role in regulating biological function of human APOBEC3G through molecular modeling and biological assay.
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通过分子建模和生物测定对loop7基序进行鉴定和表征及其在调节人APOBEC3G生物学功能中的作用。
DOI：
10.1016/j.apsb.2017.05.002
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Cen S
中科院分区：
文献类型：
--
作者：
Zhai C;Ma L;Zhang Z;Ding J;Wang J;Zhang Y;Li X;Guo F;Yu L;Zhou J;Cen S
人 APOBEC3G (hA3G) 是一种胞苷脱氨酶，可抑制 HIV-1 复制。 HIV-1 辅助蛋白病毒感染因子 (Vif) 通过靶向 hA3G 进行蛋白酶体降解来抵消 hA3G。在这项工作中，我们构建并优化了 hA3G 二聚体和 hA3G-Vif 复合物的分子模型。分子模型研究表明hA3G的loop7基序出现在hA3G-Vif复合物和hA3G二聚体的界面上。生化分析提供的证据表明，Vif 与 hA3G 的结合导致 hA3G 二聚化的空间阻断，这意味着单体 hA3G 作为 Vif 介导的降解的底物。此外，我们还提供了loop7基序，尤其是该区域内的中心残基在hA3G二聚化、hA3G-Vif相互作用、Vif介导的hA3G降解以及hA3G的亚细胞定位中的重要作用的证据。这项工作强调了由loop7基序形成的多任务界面，它调节hA3G的生物学功能，从而提供了通过靶向loop7周围的假定位点来阻断Vif介导的A3G降解策略的可行性。分子模型研究表明，hA3G的loop7基序出现在hA3G-Vif复合物和hA3G二聚体的界面上，生化分析提供了证据支持Vif与hA3G的结合导致hA3G二聚化的空间阻断。
Human APOBEC3G (hA3G) is a cytidine deaminase which inhibits HIV-1 replication. The HIV-1 accessory protein viral infectivity factor (Vif) counteracts with hA3G by targeting it for proteasomal degradation. In this work, we constructed and optimized molecular models of the hA3G dimer and the hA3G–Vif complex. The molecular modeling study revealed that the loop7 motif of hA3G appears on the interfaces of both the hA3G–Vif complex and the hA3G dimer. Biochemical analysis provided evidence suggesting that binding of Vif to hA3G results in steric blocking of hA3G dimerization, implying that monomeric hA3G serves as a substrate for Vif-mediated degradation. Furthermore, we presented evidence for the important roles of the loop7 motif, especially the central residues within the region, in hA3G dimerization, hA3G--Vif interaction, Vif-mediated hA3G degradation as well as subcellular localization of hA3G. This work highlights a multiple-task interface formed by loop7 motif, which regulates biological function of hA3G, thus providing the feasibility of the strategy of blocking Vif-mediated A3G degradation by targeting the putative site around loop7. The molecular modeling study revealed that the loop7 motif of hA3G appears on the interfaces of both the hA3G–Vif complex and the hA3G dimer, and the biochemical analysis provided evidence supporting that binding of Vif to hA3G results in steric blocking of hA3G dimerization.
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