pH-dependent conformational change within the Lassa virus transmembrane domain elicits efficient membrane fusion.

Abstract

Lassa virus (LASV) is the most prevalent member of the arenavirus family and the causative agent of Lassa fever, a viral hemorrhagic fever. Although there are annual outbreaks in West Africa, and recently isolated cases worldwide, there are no current therapeutics or vaccines, which poses LASV as a significant global public health threat. One of the key steps in LASV infection is the delivery of its genetic material by fusing its viral membrane with the host cell membrane. This process is facilitated by significant conformational changes within glycoprotein 2 (GP2), yielding distinct prefusion and postfusion structural states. However, structural information is missing to understand the changes that occur in the transmembrane domain during the fusion process. Here, we used CD and NMR spectroscopy to show that the transmembrane domain has pH-dependent conformational changes that result in an extension of the alpha helix at the N-terminal end. Proline mutants of key residues in that region prevent the helical extension, as seen in CD and NMR. We developed a modified lipid mixing assay to study the importance of this extension on the function of GP2. Our assay shows that membrane fusion efficiency is optimal at low pH values but introducing the proline mutants results in lower fusion efficiency. These results indicate that these pH-dependent conformational changes are important to the fusion mechanism. This information can be used to design therapeutics to combat Lassa virus infections and prevent its potential spread.

• Authors: Patrick M Keating, Nicholas P Schifano, Xinrui Wei, Matthew Y Kong, Jinwoo Lee
• Journal: Biochimica et biophysica acta. Biomembranes (Biochim Biophys Acta Biomembr) Vol. 1866 Issue 1 Pg. 184233 (01 2024) ISSN: 1879-2642 [Electronic] Netherlands
• PMID: 37734457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• Proline

Topics

• Humans
• Lassa virus (genetics, metabolism)
• Membrane Fusion
• Lassa Fever (prevention & control)
• Hydrogen-Ion Concentration
• Proline