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UNC-45 (uncoordinated mutant number 45) is a UCS (UNC-45, CRO1, She4p) 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 nonmuscle tissues. Vertebrates possess one gene expressed in striated muscle (unc-45b) and another that is more generally expressed (unc-45a). Structurally, UNC-45 is composed of a series of α-helices connected by loops. It has an N-terminal tetratricopeptide repeat 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 chapter, 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.
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