title: Expansion of the fusion stalk and its implication for biological membrane fusion.
abstract: Over the past 20 years, it has been widely accepted that membrane fusion proceeds via a hemifusion step before opening of the productive fusion pore. An initial hourglass-shaped lipid structure, the fusion stalk, is formed between the adjacent membrane leaflets (cis leaflets). It remains controversial if and how fusion proteins drive the subsequent transition (expansion) of the stalk into a fusion pore. Here, we propose a comprehensive and consistent thermodynamic understanding in terms of the underlying free-energy landscape of stalk expansion. We illustrate how the underlying free energy landscape of stalk expansion and the concomitant pathway is altered by subtle differences in membrane environment, such as leaflet composition, asymmetry, and flexibility. Nonleaky stalk expansion (stalk widening) requires the formation of a critical trans-leaflet contact. The fusion machinery can mechanically enforce trans-leaflet contact formation either by directly enforcing the trans-leaflets in close proximity, or by (electrostatically) condensing the area of the cis leaflets. The rate of these fast fusion reactions may not be primarily limited by the energetics but by the forces that the fusion proteins are able to exert.
authors.affiliation: Theoretical and Computational Biophysics Department, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; andLeibniz Institute of Surface Modification, D-04318 Leipzig, Germany hrissel@gwdg.de.
authors.forename: Herre Jelger
authors.initials: HJ
authors.lastname: Risselada
authors.affiliation: Theoretical and Computational Biophysics Department, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; and.
authors.forename: Gregory
authors.initials: G
authors.lastname: Bubnis
authors.affiliation: Theoretical and Computational Biophysics Department, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; and.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
mesh_terms: D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D008561:Membrane Fusion; D008956:Models, Chemical
keywords: SNARE; diaphragm; hemagglutinin; hemi; neuronal