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Small Molecule Control of HMG-CoA Reductase Degradation: The Dark Side of Allostery


Protein quality control is an essential set of processes which allow cells to detect and mange misfolded proteins. Deficits in protein quality control increase with aging and are associated with disease, from inborn disorders to neurodegeneration and cancer. One arm of quality control is endoplasmic reticulum (ER) associated degradation (ERAD) a pathway which identifies and ubiquitinates ER and secretory pathway proteins. The conserved E3 ligase Hrd1 catalyzes the ubiquitination of a variety of misfolded substrates, but was discovered for the regulated degradation of HMG-CoA reductase, a critical sterol pathway enzyme, in yeast. The yeast isozyme Hmg2 is degraded when flux through the sterol pathway is high and stabilized when levels of pathway molecules fall. Work in our laboratory found that under degradation conditions, Hmg2 takes on some of the features of a misfolded protein, including becoming more susceptible to proteolysis in vitro. Because of the clinical importance of sterols and protein quality control in general, and because of questions about how quality control pathways distinguish misfolded proteins from the structural diversity in the cell, we are interested in learning more about how Hmg2 transitions between its normal and misfolded states. In this work, we found that the isoprenoid GGPP causes direct, reversible misfolding of Hmg2. This action is potent, specific for GGPP’s structure, and antagonizable with a similar molecule. In response to GGPP, Hmg2 takes on the features of a misfolded protein. Its structure becomes more accessible to proteases and detergents, it is degraded by ERAD, and these effects are reversible by treatment with chemical chaperones. Hmg2 is a multimer, and its multimerization is unchanged by GGPP treatment. These actions require the sterol sensing domain (SSD), a domain found in many human disease proteins. SSD mutations prevent Hmg2 misfolding in cis and even in wild type Hmg2 in trans. Taking these findings together, we liken Hmg2 misfolding to allostery, with an output of misfolding.

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