Abstract
Paramyxovirus hemagglutinin-neuraminidase (HN) plays roles in viral entry and maturation, including binding to sialic acid receptors, activation of the F protein to drive membrane fusion, and enabling virion release during virus budding. HN can thereby directly influence virulence and in a subset of avirulent Newcastle disease virus (NDV) strains, such as NDV Ulster, HN must be proteolytically activated to remove a C-terminal extension not found in other NDV HN proteins. Ulster HN is 616 amino acids long and the 45 amino acid C-terminal extension present in its precursor (HN0) form has to be cleaved to render HN biologically active. Here we show that Ulster HN contains an inter-subunit disulfide bond within the C-terminal extension at residue 596, which regulates HN activities and neuraminidase (NA) domain dimerization. We determined the crystal structure of the dimerized NA domain containing the C-terminal extension, which extends along the outside of the sialidase β-propeller domain and inserts C-terminal residues into the NA domain active site. The C-terminal extension also engages a secondary sialic acid binding site present in NDV HN proteins, which is located at the NA domain dimer interface, that most likely blocks its attachment function. These results clarify how the Ulster HN C-terminal residues lead to an auto-inhibited state of HN, the requirement for proteolytic activation of HN0 and associated reduced virulence.
Highlights
Newcastle disease virus (NDV) belongs to the large and diverse family of paramyxoviruses, which is responsible for many human and animal diseases [1]
Certain avirulent strains of NDV, such as NDV Ulster, express a longer HN protein with a C-terminal segment that must be proteolytically cleaved to fully activate the protein
We demonstrate that the extra C-terminal 45 amino acids of NDV Ulster HN adopt a well-defined structure, not present in the shorter HN proteins from virulent strains, that blocks two key receptor binding regions necessary for attachment to cells and virus entry
Summary
Newcastle disease virus (NDV) belongs to the large and diverse family of paramyxoviruses, which is responsible for many human and animal diseases [1]. Virulent strains can cause a contagious disease with respiratory, neurological and digestive tract pathology, with the most severe infections leading to substantial economic losses in the poultry industry, despite aggressive vaccination programs. Virulent velogenic viscerotropic NDV strains, known as exotic NDV (END) strains, not endemic in the US, have caused severe disease outbreaks, such as the 1971 outbreak that required the killing of over 12 million chickens at a cost of $56 million with additional costs over a 4 year cleanup. Continuing concerns about the severe economic impact of NDV outbreaks has led to the classification of NDV strains with an intracerebral pathogenicity index of .0.7, or containing a fusion protein with a multibasic cleavage site, as a U.S Department of Agriculture Select Agent [2,3]. It has been shown that NDV is able to selectively kill tumor cells, suggesting it could be useful as an oncolytic agent, and NDV is being investigated as a potential vaccine vector (reviewed in [4])
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