Distinct Structural Feature of Interacting Membrane Domains Towards Viral Fusogenecity-Coronavirus and Arenavirus

Speaker: Dr. Jinwoo Lee, UMCP

Host: Dr. Jeffery Klauda, UMCP

Abstract: The pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has emphasized the glaring necessity to study emerging viruses in preparation for the next pandemic. One such virus is Lassa virus (LASV), an Arenavirus endemic to West Africa that the World Health Organization (WHO) has declared to require prioritized research due to its pandemic potential. A critical step in the viral life cycle is membrane fusion, a process that facilitates the delivery of the viral genetic material into the target cell. The initiation of fusion of both viruses relies on a small domain within the viral glycoprotein, consisting of highly conserved, predominantly hydrophobic amino acids known as the fusion domain (FD). Intriguingly, both the Arenavirus and Coronavirus families contain the same structurally distinct FD with both an N-terminal fusion peptide  (FP)and internal fusion loop (FL), two fusogenic motifs which has never before been observed in conjunction. Improving our understanding of the underlying chemistry concerning the FD will fill major knowledge gaps in the molecular mechanism of SARS-CoV-2 and LASV fusion and aid in future endeavors regarding the viruses. The goal is to understand the structural and functional roles of multiple fusogenic regions within the SARS-CoV-2 and LASV FD and how environmental conditions impact this. We aim to use a cyclic approach to decipher how the FD initiates fusion that utilizes solution NMR to elucidate the structural rearrangement of the FD, followed by thermodynamic and kinetic investigation through ITC and a FRET-based fusion assay. This approach will permit us to investigate the structure-function relationship of the FD as a peptide and within the context of the viral glycoprotein, a novel approach that offers more physiological relevance to our results. Furthermore, the results will shed light on the molecular details integral to membrane fusion, filling a significant knowledge gap regarding how the structure-function of the SARS-CoV-2 and LASV FD contribute to this process.

Biophysics Seminar