Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme

Gregorio Gil, Jerry R. Faust, Daniel J. Chin, Joseph L. Goldstein, Michael S. Brown

Research output: Contribution to journalArticle

246 Scopus citations

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is a single polypeptide chain with two contiguous domains: a soluble domain (548 amino acids) that catalyzes the rate-controlling step in cholesterol synthesis and a membrane-bound domain (339 amino acids) that anchors the protein to the endoplasmic reticulum (ER). HMG CoA reductase is degraded at least 10-fold more rapidly than other ER proteins; degradation is accelerated in the presence of cholesterol. To understand this controlled degradation, we transfected reductase-deficient Chinese hamster ovary (CHO) cells with a plasmid expression vector containing a reductase cDNA that lacks the segment encoding the membrane domain. The plasmid produced a truncated reductase (37 kd smaller than normal) that was enzymatically active with normal kinetics; most of the truncated enzyme was found in the cytosol. The truncated enzyme was degraded one-fifth as fast as the holoenzyme; degradation was no longer accelerated by sterols. We conclude that the membrane-bound domain of reductase plays a crucial role in the rapid and regulated degradation of this ER protein.

Original languageEnglish (US)
Pages (from-to)249-258
Number of pages10
JournalCell
Volume41
Issue number1
DOIs
StatePublished - May 1985

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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