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Journal of Virology, June 2003, p. 6913-6922, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6913-6922.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Fusion Deficiency Induced by Mutations at the Dimer Interface in the Newcastle Disease Virus Hemagglutinin-Neuraminidase Is due to a Temperature-Dependent Defect in Receptor Binding

Elizabeth A. Corey,1 Anne M. Mirza,1 Elizabeth Levandowsky,1,2 and Ronald M. Iorio1*

Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0122,1 Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, Massachusetts 016092

Received 27 November 2002/ Accepted 25 March 2003

The tetrameric paramyxovirus hemagglutinin-neuraminidase (HN) protein mediates attachment to sialic acid-containing receptors as well as cleavage of the same moiety via its neuraminidase (NA) activity. The X-ray crystallographic structure of an HN dimer from Newcastle disease virus (NDV) suggests that a single site in two different conformations mediates both of these activities. This conformational change is predicted to involve an alteration in the association between monomers in each HN dimer and to be part of a series of changes in the structure of HN that link its recognition of receptors to the activation of the other viral surface glycoprotein, the fusion protein. To explore the importance of the dimer interface to HN function, we performed a site-directed mutational analysis of residues in a domain defined by residues 218 to 226 at the most membrane-proximal part of the dimer interface in the globular head. Proteins carrying substitutions for residues F220, S222, and L224 in this domain were fusion deficient. However, this fusion deficiency was not due to a direct effect of the mutations on fusion. Rather, the fusion defect was due to a severely impaired ability to mediate receptor recognition at 37°C, a phenotype that is not attributable to a change in NA activity. Since each of these mutated proteins efficiently mediated attachment in the cold, it was also not due to an inherent inability of the mutated proteins to recognize receptors. Instead, the interface mutations acted by weakening the interaction between HN and its receptor(s). The phenotype of these mutants correlates with the disruption of intermonomer subunit interactions.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave., No., Worcester, MA 01655-0122. Phone: (508) 856-5257. Fax: (508) 856-5920. E-mail: Ronald.Iorio{at}umassmed.edu.

Journal of Virology, June 2003, p. 6913-6922, Vol. 77, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.12.6913-6922.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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