Annexin proteins involved in plasma membrane repair reshape a membrane edge: Direct evidence from molecular simulations.

Abstract

The Annexin (ANX) family of Ca+2-dependent membrane-binding proteins are implicated in plasma membrane repair in animal cells. The inward flux of Ca+2 upon formation of a plasma membrane lesion/pore drives the binding of cytoplasmic ANX proteins to the membrane, close to the pore. Annexins are deemed responsible for plasma membrane repair and are overexpressed in cancer cells where the plasma membrane is in the need for frequent repair. Annexin A5 (ANXA5) trimers form crystalline arrays solid-supported membranes (1), and owing to their concave disc-like shape, induce negative curvature on a flat plasma membrane (2), and are therefore likely to reshape the membrane in the vicinity of the membrane pore to support membrane repair (3). However, no direct evidence of membrane shaping has yet emerged. Here, we simulate ANXA5 binding on a bicelle, which models a membrane pore under periodic boundary conditions, and demonstrate that increasing concentration of ANXA5 trimers induces a monotonically increasing out-of-plane upward curvature in the bicelle. Interestingly, this overall curvature amounts to half the curvature induced by a single ANXA5 trimer on a flat lipid bilayer. The out of plane curvature induced by ANXA5 trimers near a membrane pore is demonstrated for the first time. Our results have important implications in the membrane-reshaping properties of Annexins and their ability to repair membranes.