Structural Rearrangements of the Central Region of the Morbillivirus Attachment Protein Stalk Domain Trigger F Protein Refolding for Membrane Fusion

• Type of Material: Article
• Authors: Nadine Ader, University of Bern; Melinda A. Brindley, Emory University; Mislay Avila, University of Bern; Francesco C. Origgi, University of Bern; Johannes P. M. Langedijk, Crucell Holland BV; Claes Orvell, Karolinska University Hospital; Marc Vandevelde, University of Bern; Andreas Zurbriggen, University of Bern; Richard Plemper, Emory University; Philippe Plattet, University of Bern
• Language: English
• Date: 2012-05-11
• Publisher: The American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M112.342493
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 287
• Issue: 20
• Start Page: 16324
• End Page: 16334
• Grant/Funding Information: This work was supported by the Swiss National Science Foundation (Ref. No. 310030_132887; to P. P.); And, in part, by United States Public Health Service Grant AI083402 (to R. K. P.).
• Keywords: Hendra virus; 4-Helix bundle; Biochemistry & Molecular Biology; Newcastle disease virus; Cell fusion; Nipah virus; Life Sciences & Biomedicine; Hemagglutinin-neuraminidase protein; Canine distemper virus; Measles virus; Functional interaction; Science & Technology; Swiss model
• Research Categories: Biology, Neuroscience; Biology, Molecular; Biology, Virology; Chemistry, Biochemistry

Abstract

It is unknown how receptor binding by the paramyxovirus attachment proteins (HN, H, or G) triggers the fusion (F) protein to fuse with the plasma membrane for cell entry. H-proteins of the morbillivirus genus consist of a stalk ectodomain supporting a cuboidal head; physiological oligomers consist of non-covalent dimer-of-dimers. We report here the successful engineering of intermolecular disulfide bonds within the central region (residues 91-115) of the morbillivirus H-stalk; a sub-domain that also encompasses the putative F-contacting section (residues 111-118). Remarkably, several intersubunit crosslinks abrogated membrane fusion, but bioactivity was restored under reducing conditions. This phenotype extended equally toHproteins derived from virulent and attenuated morbillivirus strains and was independent of the nature of the contacted receptor. Our data reveal that the morbillivirus H-stalk domain is composed of four tightly-packed subunits. Upon receptor binding, these subunits structurally rearrange, possibly inducing conformational changes within the central region of the stalk, which, in turn, promote fusion. Given that the fundamental architecture appears conserved among paramyxovirus attachment protein stalk domains, we predict that these motions may act as a universal paramyxovirus F-triggering mechanism.