Role of the Influenza M2 Protein on Viral Budding and Scission

Date
2017-12-22
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Abstract
The budding of enveloped viruses is a complex multi-step process requiring alterations in membrane curvature and scission at the neck of the budding virion. M2 is a pH-dependent matrix protein from influenza virus widely known for its role in viral uncoating and the target of the amantadine flu drug that prevents proton transport. An additional role played by M2 relies on collective effects where M2 clusters have been hypothesized to induce local membrane curvature, resulting in a reduced energetic cost associated with the bending of the membrane and where the budding of virus particles takes place in a cholesterol-dependent manner (Rossman et al., Cell 142, pp. 902-913, 2010). The additional M2 role is striking in that many viruses utilize host endosomal sorting complex (ESCRT) proteins for virus budding. However, it was found that the mechanism for influenza can be ESCRT-independent. MD simulations (MD) were used to study the behavior of Influenza M2 proteins at various aggregation conditions and embedded in model lipid membranes. The study of this protein presented a unique challenge in that it has a dual role, and epitomizes a frontier of problems in biology where proteins have additional, unsuspected roles, and require a combination of techniques to uncover their function. Our general philosophy to tackle the aggregation of proteins at the mesoscopic level, consists in first, the combination of atomistic-level molecular simulation techniques to investigate the details of molecular interactions. Coarse-grained simulations are then used to extract free energies between protein pairs mediated by lipids. The calculation of membrane induced fingerprints enabled us to propose a scheme that may be used to study membrane induced curvature via cooperative interactions from multiple proteins whether these belong to the same kind or in combination with any other transmembrane protein types. The approach taken is relevant because the calculation of the energetics of membrane topology transformations is beyond the realm of possibility for standard molecular dynamics simulations.
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Keywords
membrane virus budding scission influenza
Citation
Mendez-Villuendas, E. (2017). Role of the Influenza M2 Protein on Viral Budding and Scission (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.