Molecular mechanics of calcium–myristoyl switches

Many eukaryotic cellular and viral proteins have a covalently attached myristoyl group at the amino terminus. One such protein is recoverin, a calcium sensor in retinal rod cells, which controls the lifetime of photoexcited rhodopsin by inhibiting rhodopsin kinase1,2,3,4,5,6. Recoverin has a relative molecular mass of 23,000 (Mr 23K), and contains an amino-terminal myristoyl group (or related acyl group) and four EF hands7. The binding of two Ca2+ ions to recoverin leads to its translocation from the cytosol to the disc membrane8,9. In the Ca2+-free state, the myristoyl group is sequestered in a deep hydrophobic box, where it is clamped by multiple residues contributed by three of the EF hands10. We have used nuclear magnetic resonance to show that Ca2+ induces the unclamping and extrusion of the myristoyl group, enabling it to interact with a lipid bilayer membrane. The transition is also accompanied by a 45-degree rotation of the amino-terminal domain relative to the carboxy-terminal domain, and many hydrophobic residues are exposed. The conservation of the myristoyl binding site and two swivels in recoverin homologues from yeast to humans indicates that calcium–myristoyl switches are ancient devices for controlling calcium-sensitive processes.