Thermally Induced Structural Changes in an Armadillo Repeat Protein Suggest a Novel Thermosensor Mechanism in a Molecular Chaperone

Abstract

Molecular chaperones are commonly identified by their ability to suppress heat induced protein aggregation. The muscle specific molecular chaperone UNC-45B is known to be critical in folding myosin and is trafficked to the sarcomeres A-band during thermal stress. Here, we identify thermally dependent structural changes in the UCS chaperone domain of UNC-45B that occur in the physiologically relevant heat shock range. We show that distinct changes to the armadillo repeat protein topology result in exposure of hydrophobic patches, and increased flexibility of the molecule. These rearrangements suggest a novel thermosensor within the chaperone domain of UNC-45B. We propose that these changes may be central to the molecular mechanism of UNC-45B chaperone activity. They may function to suppress aggregation under stress by allowing binding to a wide variety of aggregation prone loops on its client. This work was funded by AHA grant 13GRNT17290006 and the Cecil M. Green Endowment at the University of Texas Medical Branch.