Bicontinuous Inverted Cubic Phases as Tools for Studying the Mechanism of Membrane-Remodeling Proteins

Abstract

Membrane trafficking/remodeling involves creating and destroying membrane fusion/fission pores. The mechanisms by which pores open and close are poorly understood. Here, I point out that pores have qualitatively and quantitively different curvatures than membrane vesicles or tubules. As shown here, pores have negative Gaussian curvature, can have very low (negative) mean curvature, and large gradients in geometric mean curvature, unlike the membrane vesicles and tubules that are used to study protein curvature sensing and induction. However, bicontinuous inverted cubic (QII) phases of phospholipids have curvature properties closely resembling pores. It is known that curvature-dependent binding of trafficking proteins to membranes is involved in pore evolution. However, the binding of proteins to membranes with pore-like curvature has not been studied. Known or unknown proteins may have evolved to bind preferentially to such surfaces. Implementing a protein-binding assay using the QII phase as the substrate would cover an important blind spot in our knowledge of trafficking/remodeling. I propose a method for such an assay. Lastly, I point out that QII phases are important for studying the effects of proteins on the energy required to produce pores. The curvature elastic energy of a pore is most of the energy needed to create or destroy it. It can be estimated by studying QII phases: pore formation is favored under circumstances where the QII phase is thermodynamically stable. Proteins involved in trafficking may act partly by changing the curvature energy of nascent fusion pores. That could be determined by studying the effects of the peptides on QII stability.