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Publication Abstract from PubMed

Hendra virus (HeV) is a zoonotic paramyxovirus belonging to the genus Henipavirus. HeV is highly pathogenic, and it can cause severe neurological and respiratory illnesses in both humans and animals, with an extremely high mortality rate of up to 70%. Amongst the genes that HeV encodes, the matrix (M) protein forms an integral part of the virion structure and plays critical roles in coordinating viral assembly and budding. Nevertheless, the molecular mechanism of this process is not fully elucidated. Here, we determined the crystal structure of HeV M to 2.5 A resolution. The dimeric structural configuration of HeV M is similar to that of the Newcastle Disease virus (NDV) M, and is fundamental for protein stability and effective virus-like particle (VLP) formation. Analysis of the crystal packing revealed a notable interface between the alpha1 and alpha2 helices of neighbouring HeV M dimers, with key residues sharing degrees of sequence conservation amongst henipavirus M proteins. Structurally, a network of electrostatic interactions dominates the alpha1-alpha2 interactions, involving residues Arg57 from the alpha1 helix, and Asp105 and Glu108 from the alpha2 helix. The disruption of the alpha1-alpha2 interactions using engineered charge reversal substitutions (R57E, R57D, or E108R) resulted in significant reduction or abrogation of virus-like particle (VLP) production. This phenotype was reversible with the R57E/E108R mutant that was designed to partly restore salt-bridge contacts. Collectively, our results define and validate previously underappreciated regions of henipavirus M proteins that are crucial for productive VLP assembly.IMPORTANCE Hendra virus is a henipavirus associated with lethal infections in humans. Being classified as a biosafety level (BSL)-4 agents, there is currently no preventive or therapeutic treatments available against HeV. Vital to henipavirus pathogenesis, the structural protein M has been implicated in viral assembly and budding, as well as host-virus interactions. However, there is no structural information available for henipavirus M, and the basis of M-driven viral assembly is not fully elucidated. We demonstrate the first three-dimensional structure of a henipavirus M protein. We show the dimeric organisation of HeV M as a basic unit for higher order of oligomerisation. Additionally, we define key regions/residues of the HeV M that are required for productive virus-like particle formation. These findings provide the first insight into the mechanism of M-driven assembly in henipavirus.

Electrostatic interactions between Hendra virus matrix proteins are required for efficient virus-like particle assembly.,Liu YC, Grusovin J, Adams TE J Virol. 2018 Apr 25. pii: JVI.00143-18. doi: 10.1128/JVI.00143-18. PMID:29695428^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.