Characterizing the Lassa Virus Envelope Glycoprotein Membrane Proximal External Region for Its Role in Fusogenicity
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RESEARCH ARTICLE
Characterizing the Lassa Virus Envelope Glycoprotein Membrane Proximal External Region for Its Role in Fusogenicity Junyuan Cao1,2 • Guangshun Zhang1,3 • Minmin Zhou1,2 • Yang Liu1,2 • Gengfu Xiao1,2
•
Wei Wang1,2
Received: 30 April 2020 / Accepted: 22 July 2020 Ó Wuhan Institute of Virology, CAS 2020
Abstract The membrane-proximal external region (MPER) of Lassa virus (LASV) glycoprotein complex (GPC) is critical in modulating its functionality. Till now, the high-resolution structure of the intact GPC, including MPER is not available. In this study, we used alanine substitution to scan all 16 residues located in LASV MPER. Western blotting and quantification fusion assay showed that the residues located at the C terminus of the HR2 (M414 and L415) and N terminus of the MPER (K417 and Y419) are critical for GPC-mediated membrane fusion function. Furthermore, cell surface biotinylation experiments revealed that M414A, K417A and Y419A expressed similar levels as WT, whereas L415A mutant led to a reduction of mature GPC on the cell surface. Moreover, substitution of these residues with the similar residue such as M414L, L415I, K417R and Y419F would partly compensate the loss of the fusion activity caused by the alanine mutant in these sites. Results from this study showed that several key residues in the MPER region are indispensable to promote the conformational changes that drive fusion events and shed light on the structure analysis of LASV GPC and anti-LASV therapeutics. Keywords Lassa virus (LASV) Arenavirus Glycoprotein complex (GPC) Membrane-proximal external region (MPER) Membrane fusion
Introduction Lassa virus (LASV) belongs to the Mammarenavirus genus, Arenaviridae family, causing about 300,000 cases of Lassa fever per year with the mortality rate in hospitals of 15% to 30% (Oldstone 2002; Houlihan and Behrens 2017). Mammarenaviruses are classified into the Old World (OW) arenaviruses and New World (NW) arenaviruses based mainly on virus genetics, serology, & Wei Wang [email protected] & Gengfu Xiao [email protected] 1
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
2
University of the Chinese Academy of Sciences, Beijing 100049, China
3
College of Life Sciences, Nankai University, Tianjin 300353, China
antigenic properties, and geographical relationships (Nunberg and York 2012). The OW LASV and Lujo virus (LUJV), as well as NW Junı´n virus (JUNV), Machupo virus (MACV), Guanarito virus (GTOV), and Sabia´ virus (SBAV), are known to cause severe hemorrhagic fever and are listed as biosafety level 4 (BSL-4) agents (Buchmeier et al. 2007). Arenaviruses are enveloped, negative-sense RNA viruses containing two genomic strands, S and L. L segment encodes the viral polymerase L and matrix protein (Z), while S segment encodes nucleoprotein (NP) and glycoprotein complex (GPC). During maturation, the p
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