Chemistry Department Seminar: Michael Summers, UMBC
Insights into the Mechanism of HIV-1 Genome Packaging and Assembly
University of Maryland, Baltimore County
In cells infected by HIV-1, newly synthesized retroviral Gag proteins are directed to specific cellular membranes where they assemble and bud to form immature virions. Membrane binding is mediated by Gag’s matrix (MA) domain, which contains an N-terminal myristyl group that can adopt sequestered and exposed conformations. Membane specificity is regulated by phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2), a cellular factor abundant in the inner leaflet of the plasma membrane (PM). We show that PI(4,5)P2 molecules can bind HIV-1 MA and trigger myristate exposure. The phosphoinositol moiety and one of the fatty acid chains binds to a cleft on the surface of the protein, and the other fatty acid and the exposed myristyl group bracket a conserved basic surface patch that is required for membrane binding. Thus, PI(4,5)P2 can act as both a trigger of the myristyl switch and as a membrane anchor, suggesting a structure-based mechanism for the specific targeting HIV-1 Gag to PI(4,5)P2-enriched membranes. The structural findings also explain how HIV-1 Gag is specifically targeted to lipid raft microdomains on the inner leaflet of the plasma membrane. Approximately 2,000 Gag molecules assemble to form an immature virus particle, but only a subset of molecules (perhaps 12 or fewer) is responsible for packaging the dimeric RNA genome during assembly. Insights into the protein-RNA interactions that appear to regulate pseudo-diploid genome selection will be presented.
Sponsored by Chemistry. Contact: Joe Chihade, x7446