Annexin V-crystal structure and its implications on function.

Abstract

Annexins constitute a family of cytosolic, water soluble proteins, which bind to negatively charged phospholipids in a calcium-dependent manner. They display structural and functional features of both soluble and integral membrane proteins. The annexins face the hydrophilic as well as the hydrophobic phase (Janus-faced proteins) and mediate ion transport in vitro. We present the refined structure and molecular model of annexin V at 2.0 A resolution. The molecule is almost entirely alpha-helical, and each of the four repeats of annexin V is folded into a compact domain of similar structure. The four domains are arranged in an almost planar, cyclic array. In the center of the molecule, one can find a prominent hydrophilic pore, which we associate with the calcium-selective channel found in annexin V. Annexin V has an overall flat, slightly curved shape with two faces, one convex and one concave. The three calcium binding sites Ca1 to Ca3, all located at the convex face of the molecule, are assumed to be phospholipid binding sites, as suggested by their structural similarity to the calcium site of phospholipase A2. Soluble and membrane-bound annexin have closely similar structures, as shown by electron microscopic analysis. Several other observations provide evidence that the membrane-anchoring region of the annexin V molecule is located on the convex face. In the last part of this article, the electrophysiology of the annexins is described. Ion permeation occurs in discrete conductance states and is regulated by voltage across the membrane. A model for the annexin V-membrane interaction, the ion channel formation, and the ion conduction pathway is proposed.