The experiments described in this proposal are directed toward understanding the mechanism by which """"""""viral protein U"""""""" (Vpu) mediates the exist of HIV-1 particles from cells. Dr. Panganiban's experiments described here are centered around the role of a novel cellular protein that interacts directly with Vpu in yeast, in vitro and in human cells. This novel cellular protein, """"""""U-binding protein (Ubp) is a member of a protein superfamily that includes the immunophilins and a class of serine/threonine phosphatases containing tetratrico-peptide repeats (TPRs). Dr. Panganiban and his colleagues have several complementary goals. They will carry out experiments to examine the interaction between Vpu and Ubp in more detail. In particular. In particular they will identify regions of the two proteins that are required for protein-protein interaction, isolate mutants that exhibit altered binding stability, and test the hypothesis that Vpu action is mediated via Ubp. Dr. Panganiban's preliminary data also indicated that Ubp interacts directly with Hiv-1 Gag protein in vitro, and with the capsid domain of HIV-1 Gag protein in human cells. Thus, he will identify the sites on Ubp and Gag that are required for this interaction. To examine the effect on Ubp on particle release, the effect of expression of wild type and mutant forms of Ubp and Gag that are required for this interaction. To examine the effect of Ubp on particle release, the effect of expression of wild type and mutant forms of Ubp on particle release will be determined. Similarly, they may determine whether ablation of endogenous Ubp expression affects the efficiency of particle release. Finally, since Ubp has not been previously characterized, Dr. Panganiban and his colleagues will examine the intrinsic properties of Ubp and try to gain insight into the normal role of Ubp in the cell. The overall goal of these studies to develop a comprehensive picture that accounts for the molecular mechanism by which Vpu mediates particle release.

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