Chapter 16 Regulation of Protein Activities by Fusion to Steroid Binding Domains

Abstract

This chapter discusses a novel approach that involves the posttranslational regulation of a constitutively expressed fusion protein. The method is based on the fact that the hormone binding domain (HBD) of steroid receptors can be used as an autonomous regulatory cassette to subject many heterologous protein functions to hormonal control in cis. Fusion proteins are maintained in an inactive state in the absence of hormone and are rapidly activated by addition of the cognate hormone. The hormone-reversible protein inactivation function of the HBD works by a relatively unspecific mechanism involving steric hindrance by the HSP90 complex. This method should be applicable to any protein with at least one essential function that is sensitive to steric hindrance. Hence, this regulatory system should work in the cytosolic and nuclear compartments of any organism that provides the components of the HSP90 complex. The choice of HBD is primarily dictated by the biological system rather than by the heterologous protein itself because the activation of endogenous steroid receptors is usually undesirable.