Drug Discovery Seminars
10:30 AM to 11:30 AM | May 10, 2019

Drug Discovery Seminar: James Hurley, Ph.D.

Forum Hall, Palmer Commons
This is a public event.

Refreshments will be served 

Clathrin coated vesicles begin their voyage when adaptor protein complexes engage with transmembrane receptor tails and membrane lipids, and in some cases, the small GTPase Arf1. Accessory proteins of the primate lentiviruses HIV and SIV hijack these pathways to reconfigure the cell surface to maximize viral fitness. In the course of studying how the Nef accessory protein of HIV-1 downregulates MHC-I to suppress immune recognition of infected cells, we discovered a more general principle that AP-1 clathrin adaptor complex, together with Arf1, can form lattices whose dimensions and symmetry match that of clathrin. HIV-1 Nef promotes this pre-existing process and redirects it for the benefit of the virus. Tetherin is an interferon-induced antiviral restriction factor whose sequence varies between closely related species, such that antagonism of tetherin is a major barrier to cross-species transmission of lentiviruses. During lentiviral evolution, the task of downregulating tetherin has toggled between Nef and another accessory protein, Vpu. We discovered that the Nef of O-group HIV-1 drives the formation of a unique closed trimeric assembly of AP-1 such that tetherin is sequestered at the trans-Golgi network (TGN). In contrast, sooty mangabey SIV Nef hijacks AP-2 at the plasma membrane by inducing the refolding of the first helix of the beta subunit of AP-2 into a beta sheet, which cooperates with SIVsmm Nef to create a pocket for the unique DDIWK motif of simian tetherin. These divergent mechanisms highlight the sophistication of both the clathrin adaptor machinery and viral strategies to hijack it, while suggesting the presence of druggable sites with virus-specific functions on host proteins.ᐧ

James Hurley, Ph.D.
Judy C. Webb Chair and Professor of Biochemistry, Biophysics and Structural Biology
University of California at Berkeley