Molecular mechanisms of calmodulin's functional versatility

Calmodulin (CaM) is a primary Ca2+-binding protein found in all eukaryotic cells. It couples the intracellular Ca2+ signal to many essential cellular events by binding and regulating the activities of more than 40 different p roteins and enzymes in a Ca2+-dependent manner. CaM contains two structural ly similar domains connected by a flexible central linker. Each domain of t he protein binds two Ca2+ ions with positive cooperativity. The binding of Ca2+ transforms the protein into its active form through a reorientation of the existing helices of the protein. The two helices in each helix-loop-he lix Ca2+-binding motif are almost antiparallel in Ca2+-free CaM. The bindin g of Ca2+ induces concerted helical pair movements and changes the two heli ces in each Ca2+ binding motif to a nearly perpendicular orientation. These concerted helix pair movements are accompanied by dramatic changes on the molecular surface of the protein. Rather than exhibiting a flat, hydrophili c molecular surface as seen in Ca2+-free CaM, the Ca2+-saturated form of th e protein contains a Met-rich, cavity-containing hydrophobic surface in eac h domain. These hydrophobic surfaces are largely responsible for the bindin g of CaM to its targets. The unique flexibility and high polarizability of the Met residues located at the entrance of each hydrophobic pocket togethe r with other hydrophobic amino acid residues create adjustable, sticky inte raction surface areas that can accommodate CaM's targets, which have variou s sizes and shapes. Therefore, CaM is able to bind to a large array of targ ets without obvious sequence homology. Upon binding to its target peptides, the unwinding of the central linker allows the two domains of the protein to engulf the hydrophobic face of target peptides of differing lengths. The binding of Ca2+ reduces the backbone flexibility of CaM. Formation of comp lexes with its target peptides further decreases the backbone motion of CaM .