A dual-functional paramyxovirus F protein regulatory switch segment: activation and membrane fusion

doi:10.1083/jcb.200305130

Published 27 October 2003. doi:10.1083/jcb.200305130

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© The Rockefeller University Press, 0021-9525/2003/10/363 $8.00
The Journal of Cell Biology, Volume 163, Number 2, 363-374

Article

A dual-functional paramyxovirus F protein regulatory switch segment : activation and membrane fusion

Charles J. Russell¹, Karen L. Kantor², Theodore S. Jardetzky² and Robert A. Lamb¹^,2

¹ Howard Hughes Medical Institute, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60208
² Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60208

Address correspondence to Robert A. Lamb, Dept. of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3500. Tel.: (847) 491-5433. Fax: (847) 491-2467. email: ralamb{at}northwestern.edu

Many viral fusion–mediating glycoproteins couple ${alpha}$ -helicalbundle formation to membrane merger, but have different methodsfor fusion activation. To study paramyxovirus-mediated fusion,we mutated the SV5 fusion (F) protein at conserved residuesL447 and I449, which are adjacent to heptad repeat (HR) B andbind to a prominent cavity in the HRA trimeric coiled coil inthe fusogenic six-helix bundle (6HB) structure. These analyseson residues L447 and I449, both in intact F protein and in 6HB,suggest a metamorphic region around these residues with dualstructural roles. Mutation of L447 and I449 to aliphatic residuesdestabilizes the 6HB structure and attenuates fusion activity.Mutation of L447 and I449 to aromatic residues also destabilizesthe 6HB structure despite promoting hyperactive fusion, indicatingthat 6HB stability alone does not dictate fusogenicity. Thus,residues L447 and I449 adjacent to HRB in paramyxovirus F havedistinct roles in fusion activation and 6HB formation, suggestingthis region is involved in a conformational switch.

Key Words: viral fusion proteins; membrane fusion activation; molecular models; protein conformation; antiviral agents

Abbreviations used in this paper: 6HB, six-helix bundle; CF,carboxyfluorescein; HR, heptad repeat; TM, transmembrane; vFGp,viral fusion–mediating glycoprotein; wt, wild type.

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