Inhibitor Myosin Light Chain Kinase (MLCK)
Myosin light chain kinase (MLCK), a Ca2+-calmodulin dependent multi-functional enzyme, plays a critical role in the regulation of smooth muscle contraction and cellular migration. It regulates the contractile interaction between actin microfilaments and conventional smooth muscle and non-muscle myosin II. There are three homologs of MLCK that share a similar catalytic domain. The smooth muscle (sm) MLCK is expressed ubiquitously, whereas skeletal muscle (sk) MLCK is expressed in skeletal muscle and cardiac (c) MLCK only in the cardiac tissue. The regulatory mechanisms of MLCK are also conserved in all MLCKs. MLCK is composed of an N-terminal actin-binding domain, a central kinase domain, and a C-terminal myosin-binding domain. The kinase domain activates the interaction of smooth-muscle myosin with actin by phosphorylating the myosin light chain. MLCK phosphorylates a specific site on the N-terminus of the regulatory light chain of myosin II. This phosphorylation is responsible for coupling increased Ca2+ concentration with smooth muscle contraction. In the presence of Ca2+, the C-terminal domain of calmodulin binds to the N-terminus of the calmodulinbinding sequence of MLCK followed by the binding of the N-terminal domain to the C-terminus of the calmodulin-binding sequence. MLCK is reported to bind the actin filament in a manner that also allows the simultaneous binding of the other major thin filament components; calponin, tropomyosin, etc. The binding site is suggested to be on the outside of sub-domain 1. There is approximately one MLCK molecule for every 100 actin molecules in smooth muscle and each MLCK contains at least three of the DFRXXL motifs allowing each molecule to bind three actins (Kd = 4 µM).
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