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

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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.