title: Lipid-mediated, reversible misfolding of a sterol-sensing domain protein.
abstract: 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.
authors.affiliation: Department of Biology, UCSD Division of Biological Sciences, Section of Cell and Molecular Biology, La Jolla, CA 92093, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Shearer
authors.forename: Randolph Y
authors.initials: RY
authors.lastname: Hampton
mesh_terms: D005204:Farnesol / Q000737:chemistry* / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008861:Microsomes / Q000378:metabolism; D015394:Molecular Structure; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
chemical_list: D008055:Lipids; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D005204:Farnesol; D006903:Hydroxymethylglutaryl CoA Reductases; D014357:Trypsin