HMG-CoA reductase is an ER resident protein required for cholesterol biosynthesis whose selective degradation occurs in a regulated manner in both mammalian cells and in yeast. The investigator, who as a postdoc first demonstrated HMGCoA regulated degradation in yeast, proposes here to pursue a combination of genetic, cell biological and biochemical investigations of HMG CoA reductase degradation in yeast. The investigator has identified a class of genes called HRD (HMGCoA reductase degradation genes) which is required for the regulated degradation of the Hmg2p isozyme in yeast, and he now proposes to test and refine the hypotheses he has developed. One of these genes encodes a subunit of the proteasome, implicating the proteasome in the degradation of ER proteins. The other two genes are novel but have homologs in existing databases. Specifically the aims are: (1) to perform a complete dissection of Hmg2p sequence determinants responsible for regulated degradation (2) to learn the critical features of the three HRD genes and proteins, including functional specificity, cellular location and biochemical properties (3) to test the involvement of the proteasome and ubiquitination in the HRD pathway, and (4) to discover new genes involved in the regulated degradation of Hmg2p.
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