The UNC-45 Myosin Chaperone
International Review of Cell and Molecular Biology
UNC-45 is a UCS domain protein that is critical for myosin stability and function. It likely aides in folding myosin during cellular differentiation and maintenance and protects myosin from denaturation during stress. Invertebrates have a single unc-45 gene that is expressed in both muscle and non-muscle tissues. Vertebrates possess one gene expressed in striated muscle (unc-45b) and one that is more generally expressed (unc-45a). Structurally, UNC-45 is composed of a series of alpha-helices
... nected by loops. It has an N-terminal TPR domain that binds to Hsp90 and a central domain composed of armadillo repeats. Its C-terminal UCS domain, which is also comprised of helical armadillo repeats, interacts with myosin. In this review, we present biochemical, structural and genetic analyses of UNC-45 in Caenorhabditis elegans, Drosophila melanogaster and various vertebrates. Further, we provide insights into UNC-45 functions, its potential mechanism of action and its roles in human disease. Note Added in Proof Since submission of this article, two important papers regarding UNC-45 have appeared. Bird et al. (2014) demonstrated that UNC-45b in combination with Hsp90 enhance the accumulation of properly folded myosin 15 in an insect cell/baculovirus expression system. Aggregation of the expressed myosin 15 is further obviated through binding of smooth muscle essential and regulatory light chains in lieu of calmodulin, which is myosin 15's native light chain. The resulting myosin 15 exhibited actin-stimulated ATPase activity and facilitated actin filament sliding. This approach could open the door to studying other difficult-to-express myosins. In the second paper, Bujalowski et al. (2014) found that the central domain of UNC-45b binds skeletal muscle myosin independently of the UCS domain, but with lower affinity. The two domains bind to separate locations on the myosin molecule, but the UCS domain alone confers the chaperone activity of UNC-45b. This was demonstrated using a titin reporter and atomic force microscopy as discussed in section 4.1. Dedication We dedicate this article to the memory of Dr. Henry F. Epstein, who founded the field of UNC-45 biology. His interest and support of our efforts is appreciated and missed.