Structural Studies of Alix and ESCRT Complexes in HIV-1 Budding

HIV-1 出芽中 Alix 和 ESCRT 复合物的结构研究 HIV-1 颗粒的组装和释放取决于蛋白质网络，其中包括 Alix 和 Vps4A/B，以及四种多蛋白复合物：Hrs/STAM 和 ESCRT-I、II 和 III。这些蛋白质和复合物从酵母到人类都是保守的，它们的正常功能是将单泛素化受体、酶和其他货物分选到溶酶体或液泡。该网络中测试的几种蛋白质中任何一种的失活都会阻止艾滋病毒的释放和传染性。在该项目过去的工作中，我们在单个蛋白质结构域水平上绘制了 HIV 和 ESCRT 成分之间的分子相互作用，并表征了参与这些相互作用的成分的结合亲和力和相关结构。展望未来，该项目的目标将是在体外重建 HIV-1 的组装和 ESCRT 介导的出芽，并与 NCI 的 Eric Freed 合作，设计抑制细胞中 HIV-1 出芽的方法。

Structural Studies of Alix and ESCRT Complexes in HIV-1 Budding HIV-1 particle assembly and release depend on a protein network that includes Alix and Vps4A/B, and four multiprotein complexes: Hrs/STAM and ESCRT-I, II, and III. These proteins and complexes are conserved from yeast to human, and their normal function is to sort monoubiquitinated receptors, enzymes, and other cargo to the lysosome or vacuole. Inactivation of any one of several proteins tested in this network blocks HIV release and infectivity. In past effort in this project, we mapped the molecular interactions between HIV and ESCRT components at the level of individual protein domains and characterized the binding affinities and relevant structures of the components involved in these interactions. Looking ahead, the goals of this project will be to reconstitute the assembly and ESCRT-mediated budding of HIV-1 in vitro, and, in collaboration with Eric Freed, NCI, to design means for inhibiting HIV-1 budding from cells.