The Mechanism of Membrane Fusion and Lipid Flip/Flop Explored with Model Transmembrane Helices

• Applicants: Professor Dr. Dieter Langosch; Dr. Christina Scharnagl
• Subject Area: Biophysics ; Biochemistry
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260432530

A diversity of biological processes, like membrane fusion and lipid flip/flop across membranes, are based on protein/lipid interactions. In previous work, we have developed low-complexity models - the LV-peptides - of transmembrane helices. These peptides catalyze membrane fusion and lipid flip. These functional properties depend on the backbone dynamics of the helices and the charge state of the flanking residues. In this proposal, we present testable hypotheses as to how the functional and the structural properties could be connected. We will examine these hypotheses using complementary experimental approaches and simulations in order to clarify the mechanism of membrane fusion and lipid flip. In particular, we will examine the capacity of a range of LV-helices to interact with chemically distinct lipids. First, these TMD/lipid interaction could cause lipid splay and thereby initiate membrane fusion. Second, we will assess whether the covalent stabilization of these interactions facilitates lipid flip, which would support the idea that PC lipids flip within disordered membrane domains. Third, we will test a new concept where flip of PE lipids is enabled by a coupled membrane translocation of TM helix and lipids.

• DFG Programme: Research Grants