Calmodulin regulation of smooth-muscle myosin light-chain kinase.
Calmodulin is the predominant Ca2+ receptor in all nonmuscle and smooth muscle cells. As such, it mediates the activity of more than 20 intracellular enzymes. The structure of calmodulin reveals an eight-turn helix that separates the two pairs of Ca2+ binding sites. This central region is involved in enzyme recognition and/or activation. Now that the sequence of several calmodulin-dependent enzymes is known, it has been revealed that the sequence of each calmodulin binding region is unique but bind calmodulin with equal affinity. The amino-terminal portion of this region in calmodulin-dependent protein kinases serves to inhibit the enzyme from binding substrate in the absence of calmodulin. This pseudosubstrate region is both unique and specific for each enzyme. Therefore calmodulin derepresses rather than activates protein kinases. Studies with smooth-muscle myosin light-chain kinase have identified the pseudosubstrate region. It is proposed that inhibitors directed toward this intramolecular interaction should provide novel drugs for the treatment of a variety of cardiovascular diseases that result in elevated systemic vascular resistance.
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