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Mechanism of membrane fusion induced by vesicular stomatitis virus G protein

Kim, Irene S. and Jenni, Simon and Stanifer, Megan L. and Roth, Eatai and Whelan, Sean P. J. and van Oijen, Antoine M. and Harrison, Stephen C. (2017) Mechanism of membrane fusion induced by vesicular stomatitis virus G protein. Proceedings of the National Academy of Sciences of the United States of America, 114 (1). E28-E36. ISSN 0027-8424. PMCID PMC5224367.

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The glycoproteins (G proteins) of vesicular stomatitis virus (VSV) and related rhabdoviruses (e.g., rabies virus) mediate both cell attachment and membrane fusion. The reversibility of their fusogenic conformational transitions differentiates them from many other low-pH-induced viral fusion proteins. We report single-virion fusion experiments, using methods developed in previous publications to probe fusion of influenza and West Nile viruses. We show that a three-stage model fits VSV single-particle fusion kinetics: (i) reversible, pH-dependent, G-protein conformational change from the known prefusion conformation to an extended, monomeric intermediate; (ii) reversible trimerization and clustering of the G-protein fusion loops, leading to an extended intermediate that inserts the fusion loops into the target-cell membrane; and (iii) folding back of a cluster of extended trimers into their postfusion conformations, bringing together the viral and cellular membranes. From simulations of the kinetic data, we conclude that the critical number of G-protein trimers required to overcome membrane resistance is 3 to 5, within a contact zone between the virus and the target membrane of 30 to 50 trimers. This sequence of conformational events is similar to those shown to describe fusion by influenza virus hemagglutinin (a “class I” fusogen) and West Nile virus envelope protein (“class II”). Our study of VSV now extends this description to “class III” viral fusion proteins, showing that reversibility of the low-pH-induced transition and architectural differences in the fusion proteins themselves do not change the basic mechanism by which they catalyze membrane fusion.

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Additional Information:© 2017 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Stephen C. Harrison, November 17, 2016 (sent for review October 10, 2016; reviewed by Axel T. Brunger and Frederick M. Hughson). Published online before print December 14, 2016, doi: 10.1073/pnas.1618883114 We thank Anna Loveland and Joe Loparo for help with TIRF microscopy and discussions; Amy Lee and David Cureton for help with virus growth and purification; Erick Matsen and Kyung-Suk Kim for initial discussions on the model; Maria Ericsson and the Harvard Medical School Cell Biology Electron Microscopy Facility; and Raffaele Potami for help with setting up parallel computing. I.S.K. acknowledges a National Science Foundation Graduate Research Fellowship. The research was supported by NIH Grant CA-13202 to S.C.H., who is an Investigator in the Howard Hughes Medical Institute. Author contributions: I.S.K., S.P.J.W., A.M.v.O., and S.C.H. designed research; I.S.K. acquired data; I.S.K., A.M.v.O., and S.C.H. analyzed data; I.S.K. and S.J. designed and implemented the kinetic model; M.L.S. and S.P.J.W. contributed new reagents; E.R. contributed new analytic tools; and I.S.K., S.J., and S.C.H. wrote the paper. Reviewers: A.T.B., Stanford University; and F.M.H., Princeton University. The authors declare no conflict of interest. This article contains supporting information online at
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NSF Graduate Research FellowshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:membrane fusion protein | virus entry | enveloped virus
Issue or Number:1
PubMed Central ID:PMC5224367
Record Number:CaltechAUTHORS:20170105-144248207
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Official Citation:Irene S. Kim, Simon Jenni, Megan L. Stanifer, Eatai Roth, Sean P. J. Whelan, Antoine M. van Oijen, and Stephen C. Harrison Mechanism of membrane fusion induced by vesicular stomatitis virus G protein PNAS 2017 114 (1) E28-E36; published ahead of print December 14, 2016, doi:10.1073/pnas.1618883114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73281
Deposited By: George Porter
Deposited On:06 Jan 2017 17:00
Last Modified:02 Jun 2020 20:17

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