4v23
RSV Matrix protein
Structural highlights
FunctionMATRX_HRSVA Has a crucial role in virus assembly and budding. The matrix interacts with the RNP complex and this association serves two functions: facilitate virion assembly and inhibit the viral transcriptase activity. Early in infection, M is localized to the nucleus and may inhibit host cell transcription. Later on, M can associate with lipid rafts supposely by interacting with the cytoskeleton and with the cytoplasmic tail of glycoprotein G. The binding of M to host membrane is stabilized by the surface expression of the viral glycoproteins. These interactions may allow virus formation by mediating association of the nucleocapsid with the nascent envelop.[1] Publication Abstract from PubMedRespiratory syncytial virus (RSV) infects epithelial cells of the respiratory tract and is a major cause of bronchiolitis and pneumonia in children and the elderly. The virus assembles and buds through the plasma membrane, forming elongated membrane filaments, but details of how this happens remain obscure. Oligomerization of the matrix protein (M) is a key step in the process of assembly and infectious virus production. In addition, it was suggested to affect fusion protein conformation in the mature virus, the major current target for RSV antivirals. The structure and assembly of M are thus key parameters in the RSV antiviral development strategy. The structure of RSV M was previously published as a monomer. Other paramyxovirus M proteins have been shown to dimerize and biochemical data suggest that RSV M also dimerizes. Here, using Size Exclusion Chromatography - Multi Angle Light Scattering, we show that the protein is dimeric in solution. We also crystallized M in two crystal forms and show that it assembles into equivalent dimers in both lattices. Dimerization interface mutants destabilize the M dimer in vitro. To assess the biological relevance of dimerization, we used confocal imaging to show that dimerization interface mutants of M fail to assemble into viral filaments on the plasma membrane. Additionally, M mutants that fail to form filaments prevent budding and release of virus-like particles. Importantly, we show that M is biologically active as a dimer and that the switch from M dimers to higher oligomers triggers viral filament assembly and virus production. IMPORTANCE: Human respiratory syncytial virus (RSV) is the most frequent cause of infantile bronchiolitis and pneumonia. The enormous burden of RSV makes it a major unmet target for a vaccine and anti-viral drug therapy. Oligomerization of the matrix protein is a key step in the process of assembly and production of infectious virus, but the molecular mechanism of RSV assembly is still poorly understood. Here we show that RSV matrix forms dimers in solution and in crystals; the dimer is essential for formation of higher order oligomers. Destabilizing the dimer interface resulted in loss of RSV filament formation and lack of budding of virus-like particles. Importantly, our findings can potentially lead to new structure-based RSV inhibitors targeting the assembly process. Dimerization of Matrix protein is required for budding of Respiratory Syncytial Virus.,Forster A, Maertens GN, Farrell PJ, Bajorek M J Virol. 2015 Feb 11. pii: JVI.03500-14. PMID:25673702[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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