Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Electrostatic interactions between Hendra virus matrix proteins are required for productive virus-like-particle assembly (#257)

YU CHIH LIU , Julian Grusovin , Tim Adams

Hendra virus (HeV) is a zoonotic paramyxovirus belonging to henipavirus genus. HeV is highly pathogenic, and it can cause severe respiratory illnesses in both humans and animals, with an extremely high mortality rate of up to 70%.  Among the genes HeV encodes, the matrix (M) protein comprises an integral part of the viron structure, governing viral assembly and budding. However, the molecular mechanism of this process is not fully elucidated. Here, using recombinant HeV M together with X-ray crystallography, we determined the three dimensional structure of HeV M to 2.5 Å resolution. The dimeric structure of HeV M resembles to that of the Newcastle Disease Virus M protein, the closest matrix protein with an available structure within the family of Paramyxoviridae, despite limited sequence identity (~20%). Analysis of the crystal packing revealed a notable interface between the a1 and a2 helices of abutting M dimers, mediated largely via electrostatic interactions. Three key residues are involved in stabilizing this polar interface, including Arg57, Asp105 and Glu108, all of which share degrees of sequence conservation across henipavirus Ms. Using structurally guided mutagenesis and immunochemistry, we demonstrated that the disruption of the a1-a2 interface, via engineered charge-reversal HeV M mutants (R57E, R57D, or E108R), resulted in significant reduction or abrogation of virus-like-particle (VLP) production. This phenotype could be partly restored with a rescue mutant (R57E/E108R)carrying engineered salt-bridge pair. Collectively, our results have defined and validated previously underappreciated regions of HeV M crucial for productive VLP assembly.