The motor function of vertebrate myosin-5a is inhibited by its tail in a Ca²⁺-dependent manner. We previously demonstrated that the calmodulin (CaM) bound to the first isoleucine-glutamine (IQ) motif (IQ1) of myosin-5a is responsible for the Ca²⁺-dependent regulation of myosin-5a. We have solved the crystal structure of a truncated myosin-5a containing the motor domain and IQ1 (MD-IQ1) complexed with Ca²⁺-bound CaM (Ca²⁺-CaM) at 2.5-Å resolution. Compared with the structure of the MD-IQ1 complexed with essential light chain (an equivalent of apo-CaM), MD-IQ1/Ca²⁺-CaM displays large conformational differences in IQ1/CaM and little difference in the motor domain. In the MD-IQ1/Ca²⁺-CaM structure, the N-lobe and the C-lobe of Ca²⁺-CaM adopt an open conformation and grip the C-terminal and the N-terminal portions of the IQ1, respectively. Remarkably, the interlobe linker of CaM in IQ1/Ca²⁺-CaM is in a position opposite that in IQ1/apo-CaM, suggesting that CaM flip-flops relative to the IQ1 during the Ca²⁺ transition. We demonstrated that CaM continuously associates with the IQ1 during the Ca²⁺ transition and that the binding of CaM to IQ1 increases Ca²⁺ affinity and substantially changes the kinetics of the Ca²⁺ transition, suggesting that the IQ1/CaM complex functions as an intact Ca²⁺ sensor responding to distinct calcium signals.

http://www.pnas.org/content/113/40/E5812