Well plan to investigate the structure of the HIV-1 accessory protein Vpu within vectorially-oriented single membrane systems utilizing state-of-the-art synchrotron radiation-based x-ray scattering and cold neutron scattering techniques. The secondary and quaternary structures of Vpu's transmembrane domain, including the locations of potassium cations within this domain, and the tertiary structure of Vpu's cytoplasmic domain, including the latter's dependence on the phosphorylation of its of Ser52 and Ser56 residues, will be of particular interest. Since the transmembrane domain and its associated monovalent cation channel activity are responsible for enhancing virus release from the cell surface and its cytoplasmic domain is responsible for the phosphorylation-dependent induction of degradation of the HIV receptor CD$, the structural studies proposed are expected to provide substantial insight into the mechanism of Vpu's two independent actions involved in the course of HIV-1 infection. In addition, by so-determining the structural origin of the transmembrane domain's channel activity, a potential target for drug intervention based on the development of Vpu-specific channel blockers would be provided.
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