Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins

S. Song Albert, A. Poor Taylor, A. Abriata Luciano, S. Jardetzky Theodore, Dal Peraro Matteo*, Robert A. Lamb

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Parainfluenza virus 5 (PIV5) is an enveloped, single-stranded, negative-sense RNA virus of the Paramyxoviridae family. PIV5 fusion and entry are mediated by the coordinated action of the receptor-binding protein, hemagglutinin-neuraminidase (HN), and the fusion protein (F). Upon triggering by HN, F undergoes an irreversible ATP- and pH-independent conformational change, going down an energy gradient from a metastable prefusion state to a highly stable postfusion state. Previous studies have highlighted key conformational changes in the F-protein refolding pathway, but a detailed understanding of prefusion F-protein metastability remains elusive. Here, using two previously described F-protein mutations (S443D or P22L), we examine the capacity to modulate PIV5 F stability and the mechanisms by which these point mutants act. The S443D mutation destabilizes prefusion F proteins by disrupting a hydrogen bond network at the base of the F-protein globular head. The introduction of a P22L mutation robustly rescues destabilized F proteins through a local hydrophobic interaction between the N-terminal helix and a hydrophobic pocket. Prefusion stabilization conferred by a P22L-homologous mutation is demonstrated in the F protein of Newcastle disease virus, a paramyxovirus of a different genus, suggesting a conserved stabilizing structural element within the paramyxovirus family. Taken together, the available data suggest that movement of the N-terminal helix is a necessary early step for paramyxovirus F-protein refolding and presents a novel target for structure-based drug design.

Original languageEnglish (US)
Pages (from-to)E3844-E3851
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number27
DOIs
StatePublished - Jul 5 2016

ASJC Scopus subject areas

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