In calmodulin-IQ domain complexes, the Ca(2+)-free and Ca(2+)-bound forms of the calmodulin C-lobe direct the N-lobe to different binding sites.

We have investigated the roles played by the calmodulin (CaM) N- and C-lobes in establishing the conformations of CaM-IQ domain complexes in different Ca2+-free and Ca2+-bound states. Our results indicate a dominant role for the C-lobe in these complexes. When the C-lobe is Ca2+-free, it directs the N-lobe to a binding site within the IQ domain consensus sequence. It appears that the N-lobe must be Ca2+-free to interact productively with this site. When the C-lobe is Ca2+-bound, it directs the N-lobe to a site upstream of the consensus sequence, and it appears that the N-lobe must be Ca2+-bound to interact productively with this site. A model for switching in CaM-IQ domain complexes is presented in which the N-lobe adopts bound and extended positions that depend on the status of the Ca2+-binding sites in each CaM lobe and the compositions of the two N-lobe binding sites. Ca2+-dependent changes in the conformation of the bound C-lobe that appear to be responsible for directed N-lobe binding are also identified. Changes in the equilibria between extended and bound N-lobe positions may control bridging interactions in which the extended N-lobe is bound to another CaM-binding domain. Ca2+-dependent control of bridging interactions with CaM has been implicated in the regulation of ion channel and unconventional myosin activities.