Abstract

Marburg virus (MARV) is a lipid-enveloped negative sense single stranded RNA virus, which can cause a deadly hemorrhagic fever. MARV encodes seven proteins, including VP40 (mVP40), a matrix protein that interacts with the cytoplasmic leaflet of the host cell plasma membrane. VP40 traffics to the plasma membrane inner leaflet, where it assembles to facilitate the budding of viral particles. VP40 is a multifunctional protein that interacts with several host proteins and lipids to complete the viral replication cycle, but many of these host interactions remain unknown or are poorly characterized. In this study, we investigated the role of a hydrophobic loop region in the carboxy-terminal domain (CTD) of mVP40 that shares sequence similarity with the CTD of Ebola virus VP40 (eVP40). These conserved hydrophobic residues in eVP40 have been previously shown to be critical to plasma membrane localization and membrane insertion. An array of cellular experiments and confirmatory in vitro work strongly suggests proper orientation and hydrophobic residues (Phe281, Leu283, and Phe286) in the mVP40 CTD are critical to plasma membrane localization. In line with the different functions proposed for eVP40 and mVP40 CTD hydrophobic residues, molecular dynamics simulations demonstrate large flexibility of residues in the EBOV CTD whereas conserved mVP40 hydrophobic residues are more restricted in their flexibility. This study sheds further light on important amino acids and structural features in mVP40 required for its plasma membrane localization as well as differences in the functional role of CTD amino acids in eVP40 and mVP40.

Highlights

  • Marburg virus (MARV), a close relative of Ebola virus (EBOV), belongs to the Filoviridae family of viruses

  • We hypothesized the conservation of hydrophobic character in this carboxy-terminal domain (CTD) region, despite difference in positioning and secondary structure with EBOV VP40 (eVP40), may play an important role in matrix protein VP40 (mVP40) plasma membrane trafficking or assembly and budding

  • Our findings indicate the mVP40 CTD hydrophobic loop consisting of residues

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Summary

Introduction

Marburg virus (MARV), a close relative of Ebola virus (EBOV), belongs to the Filoviridae family of viruses. Filoviruses have a host plasma membrane-derived lipid envelope that gives rise to filamentous virions that can vary in their overall morphology (e.g., hooked, six-shaped or round) [2]. VP40 is a peripheral membrane protein that coats the inner leaflet of the viral lipid envelope forming the viral matrix layer, which connects the viral NC with the lipid envelope. Inside the infected host cells, both EBOV VP40 (eVP40) and mVP40 facilitate the assembly and budding of nascent virions. Expression of either eVP40 or mVP40 in mammalian cells, in the absence of other filovirus proteins, led to the formation of filamentous virus-like particles (VLPs) that resemble the authentic virions [4,5,6,7]. Expression of either eVP40 or mVP40 in mammalian cells, in the absence of other filovirus proteins, led to the formation of filamentous virus-like particles (VLPs) that resemble the authentic virions [4,5,6,7]. eVP40 and mVP40 form dimers [8,9] using an amino-terminal domain (NTD)

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