In regulated myosins, motor and enzymatic activity are toggled between on- and off-states by a switch located on its lever arm, or regulatory domain (RD). This region consists of a long alpha-helical "heavy chain" stabilized by a "regulatory" and an "essential" light chain. The on-state is activated by phosphorylation of the regulatory light chain of smooth muscle RD, or by direct binding of Ca2+ to the essential light chain of molluscan RD. Crystal structures are available only for the molluscan RD. To understand the pathway between the on and off states in more detail, we have now also determined the crystal structure of a molluscan (scallop) RD in the absence of Ca2+. Our results indicate that loss of Ca2+ abolishes most of the interactions between the light chains and may increase flexibility of the RD heavy chain. We propose that disruption of critical links with the C-lobe of the regulatory light chain is the key event initiating the off-state in both smooth muscle and molluscan myosins.
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