Research Article: Acidic pH-Induced Conformations and LAMP1 Binding of the Lassa Virus Glycoprotein Spike

Date Published: February 5, 2016

Publisher: Public Library of Science

Author(s): Sai Li, Zhaoyang Sun, Rhys Pryce, Marie-Laure Parsy, Sarah K. Fehling, Katrin Schlie, C. Alistair Siebert, Wolfgang Garten, Thomas A. Bowden, Thomas Strecker, Juha T. Huiskonen, Ted C. Pierson.

http://doi.org/10.1371/journal.ppat.1005418

Abstract

Lassa virus is an enveloped, bi-segmented RNA virus and the most prevalent and fatal of all Old World arenaviruses. Virus entry into the host cell is mediated by a tripartite surface spike complex, which is composed of two viral glycoprotein subunits, GP1 and GP2, and the stable signal peptide. Of these, GP1 binds to cellular receptors and GP2 catalyzes fusion between the viral envelope and the host cell membrane during endocytosis. The molecular structure of the spike and conformational rearrangements induced by low pH, prior to fusion, remain poorly understood. Here, we analyzed the three-dimensional ultrastructure of Lassa virus using electron cryotomography. Sub-tomogram averaging yielded a structure of the glycoprotein spike at 14-Å resolution. The spikes are trimeric, cover the virion envelope, and connect to the underlying matrix. Structural changes to the spike, following acidification, support a viral entry mechanism dependent on binding to the lysosome-resident receptor LAMP1 and further dissociation of the membrane-distal GP1 subunits.

Partial Text

Lassa virus (LASV) is an enveloped, ambi-sense, bi-segmented RNA virus endemic throughout Western Africa and is the most lethal of all known Old World arenaviruses. Due to the high mortality rates amongst hospitalized patients (~15%), ability of the virus to be spread by aerosol, and absence of licensed protective vaccines or therapeutics to treat acute infection, LASV has been classified as a biosafety level (BSL) 4 pathogen [1].

Viral surface glycoproteins mediate entry of enveloped viruses into host cells through receptor binding and subsequent fusion of viral and cellular membranes. Therefore, the structural characterization of viral glycoproteins is of fundamental interest to understand the molecular mechanisms underlying host cell infection. LASV uses a two-step process to enter target cells during infection. Upon receptor binding at the cell surface, LASV enters the cell through late endosomes/multivesicular bodies, where GP undergoes a pH-induced switch to engage the intracellular receptor LAMP1 [11,31].

 

Source:

http://doi.org/10.1371/journal.ppat.1005418

 

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