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9.A.73.  The Virus Matrix Protein (VMP) Family 

Lipid-enveloped viruses contain a lipid bilayer coat that protects their genome and helps to facilitate entry into the host cell. Filoviruses are lipid-enveloped viruses that have up to 90% clinical fatality and include Marbug (MARV) and Ebola (EBOV). These pleomorphic filamentous viruses enter the host cell through their membrane-embedded glycoprotein and then replicate using just seven genes encoded in their negative-sense RNA genome. EBOV budding occurs from the inner leaflet of the plasma membrane (PM) and is driven by the matrix protein VP40, which is the most abundantly expressed protein of the virus. VP40 expressed in mammalian cells alone can trigger budding of filamentous virus-like particles (VLPs) that are nearly indistinguishable from authentic EBOV. VP40, such as matrix proteins from other viruses, has been shown to bind anionic lipid membranes. VP40 selectively interacts with the inner leaflet of the PM and assembles into a filamentous lipid enveloped particle (Stahelin 2014).  A loop region in the NZ-terminal domain of the protein is important for viral association with the membrane, virus assembly, budding and egress (Adu-Gyamfi et al. 2014), and VP40 induces vesiculation of phosphatidyl serine (PS)-enriched membranes (Soni and Stahelin 2014). In fact, phosphatidyl serine is essential for association of dimers to generate active hexamers followed by assembly and budding (Adu-Gyamfi et al. 2015). The VP40 structure is available (Oda et al. 2016). Phosphoinositides (PIs) are important for efficient VP40 localization to the plasma membrane. PI(4,5)P2 is essential for VP40 assembly at the plasma membrane (PM) and subsequent virus like particle formation.  It is required for formation of extensive oligomers of VP40. This suggests that PS and PI(4,5)P2 play different roles in VP40 assembly, where PS regulates formation of hexamers from VP40 dimers and PI(4,5)P2 stabilizes and/or induces extensive VP40 oligomerization (Johnson et al. 2016).  VP40 induces clustering of PS and PI in the PM (Gc et al. 2016). A cationic C-terminal domain of VP40 and structural rearrangements control its interactions with phosphatidyl serine (Del Vecchio et al. 2018). It has been shown that VP40 can induce phospholipid flipping in vitro (RV Stahelin, personal communication). Several other virus matrix proteins of the Mononegavirales have been suggested to be homologous.

 

References associated with 9.A.73 family:

Adu-Gyamfi, E., K.A. Johnson, M.E. Fraser, J.L. Scott, S.P. Soni, K.R. Jones, M.A. Digman, E. Gratton, C.R. Tessier, and R.V. Stahelin. (2015). Host Cell Plasma Membrane Phosphatidylserine Regulates the Assembly and Budding of Ebola Virus. J. Virol. 89: 9440-9453. 26136573
Adu-Gyamfi, E., S.P. Soni, C.S. Jee, M.A. Digman, E. Gratton, and R.V. Stahelin. (2014). A loop region in the N-terminal domain of Ebola virus VP40 is important in viral assembly, budding, and egress. Viruses 6: 3837-3854. 25330123
Del Vecchio, K., C.T. Frick, J.B. Gc, S.I. Oda, B.S. Gerstman, E.O. Saphire, P.P. Chapagain, and R.V. Stahelin. (2018). A cationic, C-terminal patch and structural rearrangements in Ebola virus matrix VP40 protein control its interactions with phosphatidylserine. J. Biol. Chem. 293: 3335-3349. 29348171
Gc, J.B., B.S. Gerstman, R.V. Stahelin, and P.P. Chapagain. (2016). The Ebola virus protein VP40 hexamer enhances the clustering of PI(4,5)P lipids in the plasma membrane. Phys Chem Chem Phys 18: 28409-28417. 27757455
Irie, T., J.M. Licata, and R.N. Harty. (2005). Functional characterization of Ebola virus L-domains using VSV recombinants. Virology 336: 291-298. 15892969
Johnson, K.A., G.J. Taghon, J.L. Scott, and R.V. Stahelin. (2016). The Ebola Virus matrix protein, VP40, requires phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) for extensive oligomerization at the plasma membrane and viral egress. Sci Rep 6: 19125. 26753796
Johnson, R.F., P. Bell, and R.N. Harty. (2006). Effect of Ebola virus proteins GP, NP and VP35 on VP40 VLP morphology. Virol J 3: 31. 16719918
Oda, S., T. Noda, K.J. Wijesinghe, P. Halfmann, Z.A. Bornholdt, D.M. Abelson, T. Armbrust, R.V. Stahelin, Y. Kawaoka, and E.O. Saphire. (2016). Crystal Structure of Marburg Virus VP40 Reveals a Broad, Basic Patch for Matrix Assembly and a Requirement of the N-Terminal Domain for Immunosuppression. J. Virol. 90: 1839-1848. 26656687
Radzimanowski, J., G. Effantin, and W. Weissenhorn. (2014). Conformational plasticity of the Ebola virus matrix protein. Protein. Sci. 23: 1519-1527. 25159197
Soni, S.P. and R.V. Stahelin. (2014). The Ebola virus matrix protein VP40 selectively induces vesiculation from phosphatidylserine-enriched membranes. J. Biol. Chem. 289: 33590-33597. 25315776
Stahelin, R.V. (2014). Membrane binding and bending in Ebola VP40 assembly and egress. Front Microbiol 5: 300. 24995005