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A more recent version of this article appeared on February 1, 2007

Papers In Press, published online ahead of print November 7, 2006
J. Lipid Res., doi:10.1194/jlr.M600476-JLR200
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Submitted on November 1, 2006
Accepted on November 6, 2006

Mutations within membrane domain of HMG CoA reductase confer resistance to sterol-accelerated degradation

Peter C. W. Lee, Andrew D. Nguyen, and Russell A. DeBose-Boyd

Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046

Corresponding Author: Russell.DeBose-Boyd{at}utsouthwestern.edu

The pivotal event for sterol-induced degradation of the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase is binding of its membrane domain to Insig proteins in the endoplasmic reticulum. Insigs are carriers for gp78, an E3 ubiquitin ligase that marks reductase for proteasomal degradation. We report here the isolation of mutant Chinese hamster ovary cell lines, designated SRD-16, -17, and -18, in which sterol-induced ubiquitination and degradation of reductase is severely impaired. These cells were produced by chemical mutagenesis and selection with SR-12813, a compound that mimics sterols in stimulating ubiquitination and degradation of reductase. Each SRD cell line was found to contain a point mutation in one reductase allele, resulting in substitutions of Asp for Ser-60 (SRD-16), Arg for Gly-87 (SRD-17), and Pro for Ala-333 (SRD-18). Sterols failed to promote ubiquitination and degradation of these reductase mutants, owing to their decreased affinity for Insigs. Thus, three different point mutations in reductase, all of which localize to the membrane domain, disrupt Insig binding and abolish sterol-accelerated degradation of the enzyme.


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This article has been cited by other articles:


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A. D. Nguyen, J. G. McDonald, R. K. Bruick, and R. A. DeBose-Boyd
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P. C. W. Lee, P. Liu, W.-P. Li, and R. A. DeBose-Boyd
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[Abstract] [Full Text] [PDF]


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