Lipid-mediated, reversible misfolding of a sterol-sensing domain protein.

Cellular quality control requires recognition of common features of misfolding, and so is not typically associated with the specific targeting of individual proteins. However, physiologically regulated degradation of yeast HMG-CoA reductase (Hmg2p) occurs by the HRD endoplasmic reticulum quality control pathway, implying that Hmg2p undergoes a regulated transition to a quality control substrate in response to a sterol pathway molecule. Using in vitro structural assays, we now show that the pathway derivative farnesol causes Hmg2p to undergo a change to a less folded structure. The effect is reversible, biologically relevant by numerous criteria, highly specific for farnesol structure, and requires an intact Hmg2p sterol-sensing domain. This represents a distinct lipid-sensing function for this highly conserved motif that suggests novel approaches to cholesterol management. More generally, our observation of reversible small-molecule-mediated misfolding may herald numerous examples of regulated quality control to be discovered in biology or applied in the clinic.