HMG-CoA reductase (HMGR) is the rate-limiting enzyme of sterol synthesis. HMGR is an integral membrane protein that undergoes regulated degradation by ER-associated degradation, or ERAD, in response to changing cellular demand for sterols. We originally showed that the yeast HMGR isozyme Hmg2p is regulated in a manner similar to the mammalian enzyme, allowing us to exploit unique study opportunities available in yeast. Hmg2p undergoes degradation by the HRD pathway, through the action of the Hrdlp E3 ubiquitin ligase, and the sterol pathway molecule FPP regulates HRD-dependent Hmg2p degradation. The HRD pathway also functions in ER quality control, programming the destruction of many misfolded ER proteins. Accordingly, we have proposed the structural transition hypothesis for regulation: that an FPP-derived signal causes Hmg2p to undergo transition to a structure with features of a HRD quality control substrate. We have been testing this model and at the same time increasing our understanding of the HRD pathway, developing several new biochemical assays to directly address these issues. In the current work we will 1) Continue our analysis of the HRD ubiquitin ligase complex, 2) Analyze the features of the Hmg2p protein that allow its regulation by sterol pathway signals, 3) Delineate the identity and action of the lipid signals that control Hmg2p entry into the HRD pathway. 4) Study the mechanism of retrotranslocation of HRD pathway substrates required for ERAD of Hmg2p. Hmg2p degradation lies at the interface of sterol regulation and protein quality control. Thus, our work is relevant both to understanding the cellular control of sterol synthesis, and the destruction of misfolded proteins;two areas of broad and current medical import.
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