Cryo-EM structures of alphavirus conformational intermediates in low pH–triggered prefusion states
Abstract
Alphaviruses can cause severe human arthritis and encephalitis. During virus infection, structural changes of viral glycoproteins in the acidified endosome trigger virus–host membrane fusion for delivery of the capsid core and RNA genome into the cytosol to initiate virus translation and replication. However, mechanisms by which E1 and E2 glycoproteins rearrange in this process remain unknown. Here, we investigate prefusion cryoelectron microscopy (cryo-EM) structures of eastern equine encephalitis virus (EEEV) under acidic conditions. With models fitted into the low-pH cryo-EM maps, we suggest that E2 dissociates from E1, accompanied by a rotation (∼60°) of the E2-B domain (E2-B) to expose E1 fusion loops. Cryo-EM reconstructions of EEEV bound to a protective antibody at acidic and neutral pH suggest that stabilization of E2-B prevents dissociation of E2 from E1. These findings reveal conformational changes of the glycoprotein spikes in the acidified host endosome. Stabilization of E2-B may provide a strategy for antiviral agent development.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 22, 2022
- Source ID
- 10.1073/pnas.2114119119
Entities
People
- Arthur S. Kim
- Chengqun Sun
- Chun-Liang Chen
- Geeta Buda
- Michael G. Rossmann
- Michael S. Diamond
- Richard J Kuhn
- Thomas Klose
- William B Klimstra
Organizations
- Defense Threat Reduction Agency
- National Institute of Allergy and Infectious Diseases
- Purdue University
- University of Pittsburgh
- Washington University School of Medicine
- Washington University in St. Louis