Transmembrane Helix Induces Membrane Fusion through Lipid Binding and Splay

Area of Science:

• Biochemistry
• Biophysics
• Membrane Biology

Background:

• Biological membrane fusion is a critical process in cellular function.
• Molecular dynamics simulations suggest a role for splayed lipids in membrane fusion.
• Transmembrane domains (TMDs) are key players in mediating membrane fusion events.

Purpose of the Study:

• To experimentally investigate the lipid splay hypothesis of membrane fusion.
• To examine how model transmembrane domains (TMDs) influence lipid splay and liposome fusion.
• To determine the role of specific lipids in basal and TMD-driven membrane fusion.

Main Methods:

• Liposome fusion assays were performed.
• Lipid splay was induced and measured in the presence of model TMDs.
• The effects of different lipid compositions (phosphatidylethanolamine, phosphatidylserine) were analyzed.

Main Results:

• Conformationally flexible transmembrane helices enhance outer leaflet mixing and lipid splay more effectively than rigid ones.
• Cone-shaped phosphatidylethanolamine promotes basal fusion by increasing lipid splay.
• Negatively charged phosphatidylserine inhibits fusion through electrostatic repulsion and modulates helix-driven fusion.

Conclusions:

• Transmembrane helix contribution to membrane fusion is dependent on lipid binding and subsequent lipid splay.
• Lipid composition significantly impacts both basal and helix-mediated membrane fusion.
• The lipid splay hypothesis provides a framework for understanding TMD-mediated membrane fusion.