Crystal structure of the annexin XII hexamer and implications for bilayer insertion

ANNEXINS are a family of calcium- and phospholipid-binding proteins1,2 implicated in a number of biological processes including membrane fusion3 and ion channel formation4–7. The crystal structure of the annexin XII hexamer, refined at 2.8 Å resolution, forms a concave disk with 3–2 symmetry, about 100 Å in diameter and 70 Å thick with a central hydrophilic pore. Six intermolecular Ca2+ ions are involved in hexamer formation. An additional 18 Ca2+ ions are located on the perimeter of the disk, accessible only from the side of the hexameric disk. On the basis of the hexamer structure we propose here a new mode of protein–phospholipid bilayer interaction that is distinct from the hydrophobic insertion of typical membrane proteins. This speculative model postulates the Ca2+ -dependent insertion of the hydrophilic annexin XII hexamer into phospholipid bilayers with local reorientation of the bilayer phospholipids.