Abstract
Matrix proteins are encoded by many enveloped viruses, including influenza viruses, herpes viruses, and coronaviruses. Underneath the viral envelope of influenza virus, matrix protein 1 (M1) forms an oligomeric layer critical for particle stability and pH-dependent RNA genome release. However, high-resolution structures of full-length monomeric M1 and the matrix layer have not been available, impeding antiviral targeting and understanding of the pH-dependent transitions involved in cell entry. Here, purification and extensive mutagenesis revealed protein-protein interfaces required for the formation of multilayered helical M1 oligomers similar to those observed in virions exposed to the low pH of cell entry. However, single-layered helical oligomers with biochemical and ultrastructural similarity to those found in infectious virions before cell entry were observed upon mutation of a single amino acid. The highly ordered structure of the single-layered oligomers and their likeness to the matrix layer of intact virions prompted structural analysis by cryo-electron microscopy (cryo-EM). The resulting 3.4-Å-resolution structure revealed the molecular details of M1 folding and its organization within the single-shelled matrix. The solution of the full-length M1 structure, the identification of critical assembly interfaces, and the development of M1 assembly assays with purified proteins are crucial advances for antiviral targeting of influenza viruses.
Highlights
Influenza A virus (IAV) is a major human pathogen responsible for seasonal epidemics and pandemic outbreaks
The multilayered oligomers were found to be remarkably similar to coiled structures observed in low-pH–treated and disrupted virions, which were found to display a diameter of 500 Å and comprise multiple shell layers of matrix protein 1 (M1) [6]
Extensive precedent exists for the folding of purified viral structural proteins into structures similar to those found in low-pH forms in intact virions, as in the well-known structures of influenza hemagglutinin
Summary
Influenza A virus (IAV) is a major human pathogen responsible for seasonal epidemics and pandemic outbreaks. The effectiveness of antiviral drugs against IAV has been hampered by the rapid development of drug resistance, making it important to discover novel targets within IAV to facilitate multidrug therapy or to inhibit resistance by targeting highly oligomeric viral proteins [1]. The matrix protein M1 is one of the most abundant and most highly conserved proteins of IAV. It is a small, 252-amino–acid protein composed of an α-helical N-terminal domain. All other manuscript data files are available from the Mendeley database http://dx.doi.org/10.17632/ 87pvmycwfm.
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