A novel target recognition revealed by calmodulin in complex with Ca2+-calmodulin-dependent kinase kinase

The structure of calcium-bound calmodulin (Ca2+/CaM) complexed with a 26-re sidue peptide, corresponding to the CaM-binding domain of rat Ca2+/CaM-depe ndent protein kinase kinase (CaMKK), has been determined by NMR spectroscop y. In this complex, the CaMKK peptide forms a fold comprising an alpha-heli x and a hairpin-like loop whose C-terminus folds back on itself. The bindin g orientation of this CaMKK peptide by the two CaM domains is opposite to t hat observed in all other CaM-target complexes determined so far. The N- an d C-terminal hydrophobic pockets of Ca2+/CaM anchor Trp 444 and Phe 459 of the CaMKK peptide, respectively. This 14-residue separation between two key hydrophobic groups is also unique among previously determined CaM complexe s. The present structure represents a new and distinct class of Ca2+/CaM ta rget recognition that may be shared by other Ca2+/CaM-stimulated proteins.