Abstract
The Ebola filovirus causes severe hemorrhagic fever with a high fatality rate in humans. The primary structural matrix protein VP40 displays transformer-protein characteristics and exists in different conformational and oligomeric states. VP40 plays crucial roles in viral assembly and budding at the plasma membrane of the infected cells and is capable of forming virus-like particles without the need for other Ebola proteins. However, no experimental three-dimensional structure for any filovirus VP40 cylindrical assembly matrix is currently available. Here, we use a protein-protein docking approach to develop cylindrical assembly models for an Ebola virion and also for a smaller structural matrix that does not contain genetic material. These models match well with the 2D averages of cryo-electron tomograms of the authentic virion. We also used all-atom molecular dynamics simulations to investigate the stability and dynamics of the cylindrical models and the interactions between the side-by-side hexamers to determine the amino acid residues that are especially important for stabilizing the hexamers in the cylindrical ring configuration matrix assembly. Our models provide helpful information to better understand the assembly processes of filoviruses and such structural studies may also lead to the design and development of antiviral drugs.
Highlights
The Ebola virus disease causes severe hemorrhagic fever with a high fatality rate in humans and is especially dangerous because of a lack of effective vaccines[1,2]
To better understand the cylindrical assembly of the VP40 matrix protein and its structural role in the Ebola virion, we have modeled the cylindrical assembly of VP40 using computational techniques
The VP40 monomer assembles into a dimer through N-terminal domain (NTD)-NTD interactions in solution, and VP40 dimers assemble into a hexamer through multiple steps as explained in ref.[14], and the VP40 hexamers further assemble end-to-end into linear filaments through C-terminal domain (CTD)-CTD interactions
Summary
The Ebola virus disease causes severe hemorrhagic fever with a high fatality rate in humans and is especially dangerous because of a lack of effective vaccines[1,2]. This conformational flexibility allows VP40 to display transformer-protein characteristics[13] by arranging into different configurations to perform different functions in the virus life cycle[6,14]: a butterfly-shaped dimer structure (Fig. 1B) that is essential for membrane trafficking[15], a hexameric structure (Fig. 1C) that acts as a structural building block of the cylindrical viral matrix filament[14], and an RNA-binding octameric ring structure (Fig. 1D) that controls viral transcription[11,14]. Our models provide helpful information to better understand the assembly processes of filoviruses and such structural studies may lead to the design and development of antiviral drugs
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