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Minor electrostatic changes robustly increase VP40 membrane binding, assembly, and budding of Ebola virus matrix protein derived virus-like particles.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2024 May; Vol. 300 (5), pp. 107213. Date of Electronic Publication: 2024 Mar 24. - Publication Year :
- 2024
-
Abstract
- Ebola virus (EBOV) is a filamentous negative-sense RNA virus, which causes severe hemorrhagic fever. There are limited vaccines or therapeutics for prevention and treatment of EBOV, so it is important to get a detailed understanding of the virus lifecycle to illuminate new drug targets. EBOV encodes for the matrix protein, VP40, which regulates assembly and budding of new virions from the inner leaflet of the host cell plasma membrane (PM). In this work, we determine the effects of VP40 mutations altering electrostatics on PM interactions and subsequent budding. VP40 mutations that modify surface electrostatics affect viral assembly and budding by altering VP40 membrane-binding capabilities. Mutations that increase VP40 net positive charge by one (e.g., Gly to Arg or Asp to Ala) increase VP40 affinity for phosphatidylserine and phosphatidylinositol 4,5-bisphosphate in the host cell PM. This increased affinity enhances PM association and budding efficiency leading to more effective formation of virus-like particles. In contrast, mutations that decrease net positive charge by one (e.g., Gly to Asp) lead to a decrease in assembly and budding because of decreased interactions with the anionic PM. Taken together, our results highlight the sensitivity of slight electrostatic changes on the VP40 surface for assembly and budding. Understanding the effects of single amino acid substitutions on viral budding and assembly will be useful for explaining changes in the infectivity and virulence of different EBOV strains, VP40 variants that occur in nature, and for long-term drug discovery endeavors aimed at EBOV assembly and budding.<br />Competing Interests: Conflict of interest The authors declare that they have not conflicts of interest with the contents of this article.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Amino Acid Substitution
HEK293 Cells
Hemorrhagic Fever, Ebola metabolism
Hemorrhagic Fever, Ebola virology
Mutation
Nucleoproteins
Phosphatidylinositol 4,5-Diphosphate metabolism
Phosphatidylserines metabolism
Phosphatidylserines chemistry
Protein Binding
Static Electricity
Viral Core Proteins metabolism
Viral Core Proteins chemistry
Viral Core Proteins genetics
Viral Matrix Proteins metabolism
Viral Matrix Proteins genetics
Viral Matrix Proteins chemistry
Virion metabolism
Virion genetics
Cell Membrane metabolism
Ebolavirus metabolism
Ebolavirus genetics
Virus Assembly
Virus Release
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 300
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38522519
- Full Text :
- https://doi.org/10.1016/j.jbc.2024.107213