This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.HIV-1 particle assembly and release depend on the human proteins AIP1/Alix and Vps4A/B, and four human protein 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. We have begun to systematically determine the structures of domains, proteins, and multiprotein complexes in this network, and we have already solved the structures of the Vps27 (yeast Hrs) FYVE domain, the N-terminal half of Bro1 (yeast AIP1/Alix), and the nearly intact yeast ESCRT-II complex (Vps22,Vps25, and Vps36). Over the next two years we plan to 1) solve the structure of the ESCRT-I (Vps23, Vps28, Vps37) complex from yeast or human; 2) carry out a structural and functional analysis of ESCRT-II taking our 3.6 complex structure as a starting point; 3) solve the structure of the C-terminal half of Bro1 or AIP1/Alix; and 4) characterize the membrane and viral late domain binding of AIP1/Alix. In the long term our goal is the complete structural and biochemical characterization of the entire network.
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