Structural basis for Glycan-receptor binding by mumps virus hemagglutinin-neuraminidase

Rosa Ester Forgione,Yoshiyuki Manabe,Takao Hashiguchi,Antonio Molinaro,Alba Silipo,Koichi Fukase,Cristina Di Carluccio,Roberta Marchetti,Marie Kubota

doi:10.1038/s41598-020-58559-6

Rosa Ester Forgione, Yoshiyuki Manabe + Show 7 more

Open Access

https://doi.org/10.1038/s41598-020-58559-6

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Abstract

Mumps virus is one of the main cause of respiratory illnesses in humans, especially children. Among the viral surface glycoproteins, the hemagglutinin – neuraminidase, MuV-HN, plays key roles in virus entry into host cells and infectivity, thus representing an ideal target for the design of novel inhibitors. Here we report the detailed analysis of the molecular recognition of host cell surface sialylated glycans by the viral glycoprotein MuV-HN. By a combined use of NMR, docking, molecular modelling and CORCEMA-ST, the structural features of sialoglycans/MuV-HN complexes were revealed. Evidence for a different enzyme activity toward longer and complex substrates compared to unbranched ligands was also examined by an accurate NMR kinetic analysis. Our results provide the basis for the structure-based design of effective drugs against mumps-induced diseases.

Highlights

Mumps virus is one of the main cause of respiratory illnesses in humans, especially children
Given the ability of Mumps virus (MuV)-HN to recognize and cleave α-2,3-linked sialoglycans on host cell surface, we chose to investigate the binding by MuV-HN to different substrates (Scheme S1), representative of glycosphingolipids, O-linked glycoproteins, as well as of N-linked glycans
As first step to get into the structural details of binding, we examined the kinetic mechanism of MuV-HN, i.e., the enzyme kinetic parameters were evaluated by progress curve analysis using NMR detection of products and substrates hydrolysis of 1 and 2 (Scheme S1, Fig. 1)[22]

Summary

Introduction

Mumps virus is one of the main cause of respiratory illnesses in humans, especially children. Among the viral surface glycoproteins, the hemagglutinin – neuraminidase, MuV-HN, plays key roles in virus entry into host cells and infectivity, representing an ideal target for the design of novel inhibitors. According to the WHO4, the MuVs strains are classified into 12 genotypes, designated as A to N, based on nucleotide sequence analysis[5,6] and containing genes encoding for nucleocapsid (N), phospho (P), matrix (M), fusion (F), small hydrophobic (SH), hemagglutinin-neuraminidase (HN) and large (L) proteins[7,8] Each of these proteins plays a crucial role for virus entry, replication, assembly and budding. As for the majority of paramyxoviruses, HN protein from mump virus (MuV-HN) exhibits both hemagglutinin and neuraminidase activity, playing a fundamental role in the membrane fusion process during the virus entry as well as in the release and spread of the virus[14]. Our results provide further insights into the molecular mechanisms of MuV infection, representing a step beyond into the development of more effective antiviral vaccines

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