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the final phase of HMG CoA reductase degradation, constitutes post-ubiquitination steps that include the recognition and delivery of ubiquitinated HMG CoA reductase to the proteasome for destruction. Using this
Illustration 3
Figure 2

model as a guide, a variety of biochemical approaches are being utilized to 1) reveal the mechanism for sterol-sensing in Phase I of the HMG CoA reductase degradative pathway, and 2) define Phase II of the pathway through identification of molecules recruited to the HMG CoA reductase-Insig complex in the presence of sterols.

In addition, we are also embarking upon a genetic analysis of HMG CoA reductase degradation in somatic cells by selecting for mutant cells incapable of accelerating degradation of the enzyme. The inability of the mutant cells to accelerate degradation of HMG CoA reductase forms the basis for their selection. Once obtained, the defective gene that confers the HMG CoA reductase degradation-deficient phenotype will be identified through genetic complementation and expression cloning techniques.

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