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

HIV-1萌发过程中Alix和ESCRT复合体的结构研究 HIV-1颗粒的组装和释放依赖于一个包括Alix和Vps4A/B的蛋白质网络，以及四个多蛋白复合体：HRS/STAM和ESCRT-I、II和III。这些蛋白质和复合体从酵母到人类都是保守的，它们的正常功能是将单价受体、酶和其他货物分类到溶酶体或液泡中。在这个网络中测试的几种蛋白质中的任何一种失活都会阻止艾滋病毒的释放和传染性。该项目的目标是1)在单个蛋白质结构域的水平上绘制HIV和ESCRT组件之间的分子相互作用图；2)表征参与这些相互作用的组件的结合亲和力和相关结构；以及3)与NCI的Eric Freed合作，设计抑制HIV-1从细胞中萌发的方法。 2008财年进展情况 2008年的工作集中于扩展人类ESCRT系统的结构特征，如泛素结合域项目所述，并将研究扩展到Nef-AP-2适配器复杂系统，如适配器项目报告所述。

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. The objectives of this projects are to 1) map the molecular interactions between HIV and ESCRT components at the level of individual protein domains; 2) characterize the binding affinities and relevant structures of the components involved in these interactions; and 3) in collaboration with Eric Freed, NCI, to design means for inhibiting HIV-1 budding from cells. Progress in FY2008 Efforts in 2008 concentrated on extending the structural characterization of the human ESCRT system, as described also under the ubiquitin binding domains project, and extending studies to the Nef-AP-2 adaptor complex system, as described under the adaptors project report.