Understanding how herpes simplex virus proteins UL51 and UL7 modulate focal adhesions (360G-Wellcome-098406_Z_12_A)

I will address two related questions: 1. How is mammalian intracellular membrane fusion regulated? 2. How do enveloped viruses fuse with the plasma membrane to escape infected cells? To address the first question I will study the multiprotein HOPS complex, which regulates the fusion of late endosomes and lysosomes. I will map interactions within HOPS and with partner proteins, characterising these interactions structurally and biophysically. This will illuminate molecular mechanisms by which HOPS is recruited to late endosomes and lysosomes, uncoats and physically tethers compartments destined to fuse, and modulates the SNARE activity that governs their fusion. For the second question I will concentrate initially on how hepatitis delta virus binds the coat protein clathrin. Structural and biophysical analysis of this interaction will reveal whether clathrin recruitment to viruses competes with its binding to cellular partners. During the fellowship I will develop a research programme identifying the mechanisms large DNA viruses like poxviruses or herpesviruses use to exit infected cells. I will study how they hijack cellular membrane trafficking components like SNAREs, small GTPases and exocyst complex components. I will characterise interactions between these viral and cellular proteins structurally and biophysically to elucidate the molecular determinants of enveloped virus egress.