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

Alexander G Shearer1, Randolph Y Hampton

  • 1Department of Biology, UCSD Division of Biological Sciences, Section of Cell and Molecular Biology, La Jolla, CA 92093, USA.

The EMBO Journal
|January 7, 2005
PubMed

Insights

Farnesol, a sterol pathway molecule, reversibly alters yeast HMG-CoA reductase (Hmg2p) structure, marking it for cellular quality control. This discovery suggests new strategies for cholesterol management and reveals a novel mechanism of regulated protein misfolding.

Area of Science:

  • Biochemistry
  • Cellular Biology
  • Molecular Medicine

Background:

  • Cellular quality control typically identifies common misfolding patterns, not individual proteins.
  • Regulated degradation of yeast HMG-CoA reductase (Hmg2p) involves the HRD endoplasmic reticulum quality control pathway.
  • This suggests Hmg2p transitions to a quality control substrate due to a sterol pathway molecule.

Purpose of the Study:

  • To investigate the mechanism by which Hmg2p becomes a substrate for regulated degradation.
  • To determine if specific sterol pathway molecules can induce structural changes in Hmg2p.
  • To explore the implications for cellular quality control and potential therapeutic applications.

Main Methods:

  • In vitro structural assays were employed to assess changes in Hmg2p structure.
  • The effect of farnesol on Hmg2p folding was analyzed.
  • The role of the Hmg2p sterol-sensing domain in this process was investigated.

Main Results:

  • Farnesol was shown to induce a reversible change in Hmg2p structure, leading to a less folded state.
  • This effect was specific to the farnesol structure and dependent on an intact Hmg2p sterol-sensing domain.
  • The observed misfolding was biologically relevant and occurred under physiological conditions.

Conclusions:

  • Hmg2p exhibits a novel lipid-sensing function mediated by its sterol-sensing domain.
  • Reversible small-molecule-induced misfolding represents a newly identified mechanism of regulated cellular quality control.
  • This finding opens new avenues for cholesterol management and therapeutic interventions.

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