posted on 2024-01-18, 17:36authored byHallie
N. Pennington, Daniel Birtles, Zoe W. Shi, Jinwoo Lee
Infection with Lassa virus (LASV), an Old-World arenavirus
that
is endemic to West Africa, causes Lassa fever, a lethal hemorrhagic
fever. Delivery of LASV’s genetic material into the host cell
is an integral component of its lifecycle. This is accomplished via
membrane fusion, a process initiated by a hydrophobic sequence known
as the fusion domain (FD). The LASV FD (G260–N295) consists of two structurally distinct regions: an N-terminal
fusion peptide (FP: G260–T274) and an
internal fusion loop (FL: C279–N295)
that is connected by a short linker region (P275–Y278). However, the molecular mechanisms behind how the LASV
FD initiates fusion remain unclear. Here, we demonstrate that the
LASV FD adopts a fusogenic, helical conformation at a pH akin to that
of the lysosomal compartment. Additionally, we identified a conserved
disulfide bond (C279 and C292) and salt bridge
(R282 and E289) within the FL that are pertinent
to fusion. We found that the disulfide bond must be present so that
the FD can bind to the lipid bilayer and subsequently initiate fusion.
Moreover, the salt bridge is essential for the secondary structure
of the FD such that it can associate with the lipid bilayer in the
proper orientation for full functionality. In conclusion, our findings
indicate that the LASV FD preferentially initiates fusion at a pH
akin to that of the lysosome through a mechanism that requires a conserved
salt bridge and, to a lesser extent, an intact disulfide bond within
the internal FL.