Departmental Seminar: Dr. Hong Zhou

Event Date: 4.29.2014 Day: Tuesday Time: 2:00 pm Location: 700 Fairchild Event Type: Departmental

Abstract

Regulated by pH, membrane-anchored proteins E and M play multiple roles during viral maturation and later fusion with host endosomal membrane, all controlled by shifts in pH. Although crystal structures of several conformations of the ectodomain of E (i.e., the portion of E outside the viral membrane) and a fragment of M’s precursor pr (discarded by the virus during maturation) are available, the in situ atomic structures of these proteins in the mature virion are not, obscuring how they play those pH-sensitive roles. By single-particle cryo electron microscopy, we have determined the mature dengue virus structure at 3.5Å resolution and derived an atomic model of the whole virion. Our atomic model reveals that in the mature virus at neutral extracellular pH, the N-terminal 20-amino acid segment of M (involving three pH-sensing histidines) latches and thereby prevents spring-loaded E fusion protein from prematurely exposing its fusion peptide. This M latch was fastened at an earlier stage, during maturation at acid pH in the trans-Golgi network. At a later stage, to initiate infection in response to acid pH in the late endosome, M releases the latch and exposes the fusion peptide. Thus, M serves as a multistep chaperone of E to control the conformational changes accompanying maturation and infection. These pH-sensitive interactions could serve as targets for drug discovery.