J Biol Chem 1995 Aug 11;27032:19107-13. doi: 10.1074/jbc.270.32.19107.

Molecular dissection of the role of the membrane domain in the regulated degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

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We have previously shown that the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase from hamster contains all of the sequences required for both localization to the endoplasmic reticulum and regulated degradation of the enzyme. It has been reported that the enzymatic activity and mRNA levels of HMG-CoA reductase from sea urchin embryos cultured in the presence of regulators were unchanged compared to levels in control embryos (Woodward, H.D., Allen, M.C., and Lennarz, W.J. (1988) J. Biol. Chem. 263, 18411-18418). This observation led us to investigate the possibility that the sea urchin enzyme is not subject to regulated protein turnover. Interestingly, the sea urchin enzyme shares 62% amino acid sequence identity with the hamster enzyme in the membrane domain and shares similar predicted topological features. In the current studies we have compared the degradation phenotypes of the sea urchin HMG-CoA reductase and the hamster HMG-CoA reductase in Chinese hamster ovary cells to further elucidate the role of the membrane domain in enzyme degradation in response to physiological regulators. To accomplish this, we constructed sea urchin HMGal (uHMGal), the structural equivalent of hamster HMGal (httMGal), which has the sea urchin HMG-CoA reductase membrane domain fused to Escherichia coli beta-galactosidase. The uHMGal was stably expressed in CHO cells, and we found that the degradation of uHMGal is not accelerated by sterols, and even in the absence of sterols, it is less stable than hHMGal. We also constructed chimeric hamster/sea urchin HMGal molecules to investigate which amino acid sequences from the hamster enzyme are sufficient to confer sterol-regulated degradation upon the sea urchin enzyme. Our results identify the second membrane-spanning domain of hamster enzyme as important for the regulated degradation of HMG-CoA reductase.

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Genes referenced: hmgcr LOC100887844 stk36