Mutation in the Lumenal Part of the Membrane Domain of HMG-CoA Reductase Alters Its Regulated Degradation

The involvement of ER lumenal domains of HMG-CoA reductase in the regulated degradation process was examined. For this purpose we studied three cell lines expressing HMG-CoA reductase molecules with introduced functional N-glycosylation sites located in the linker segments between transmembrane span...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 1995-01, Vol.206 (1), p.186-193
Main Authors: Sekler, M.S., Simoni, R.D.
Format: Article
Language:English
Subjects:
Animals
Asparagine
beta-Galactosidase - biosynthesis
beta-Galactosidase - metabolism
CHO Cells
Cricetinae
Endoplasmic Reticulum - metabolism
Glycosylation
Hydroxycholesterols - pharmacology
Hydroxymethylglutaryl CoA Reductases - biosynthesis
Hydroxymethylglutaryl CoA Reductases - genetics
Hydroxymethylglutaryl CoA Reductases - metabolism
Kinetics
Mevalonic Acid - pharmacology
Mutagenesis
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - metabolism
Transfection
Tunicamycin - pharmacology
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Summary:The involvement of ER lumenal domains of HMG-CoA reductase in the regulated degradation process was examined. For this purpose we studied three cell lines expressing HMG-CoA reductase molecules with introduced functional N-glycosylation sites located in the linker segments between transmembrane spans 1 and 2 (HMGal/Bins(-)), 3 and 4 (HMGal/Dins(-)) and 5 and 6 (HMGal/Fins(-)), all facing the ER lumen (Olender, E. H. and Simoni, R. D. (1992) J. Biol. Chem. 267, 4223-4235). The glycosylation insertion between spons 5 and 6 (HMGal/Fins(-)) is the only one of these mutations which eliminates regulated degradation of the enzyme. The half lives of the HMGal/Fins(-) in the presence or absence of regulatory molecules are indistinguishable. In contrast the HMGal/Bins(-) and HMGal/Dins(-) mutants show a normal pattern of regulated degradation. Tunicamycin treatment of cells expressing the HMGal/Fins(-) mutant does not significantly alter the regulation defect indicating that it is the mutation per se not the glycosylation that alters the degradation response. These results suggest that the linker segments between transmembrane spans 5 and 6 (loop F) are involved in the process of regulated degradation of HMG-CoA reductase and that the regulated degradation process may occur on the lumenal side of the ER membrane.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.1995.1026