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Sterol-accelerated degradation of HMG CoA reductase is mediated by a pair of ER-resident membrane proteins called Insig-1 and Insig-2.
Membrane Topology of HMG CoA Reductase
Figure 2

Our current data support a model in which the pathway for HMG CoA reductase degradation is divided into three distinct phases (Figure 3). In the sterol-sensing Phase I, intracellular levels of sterols are monitored by either direct binding to HMG CoA reductase, or to a membrane-bound receptor that subsequently transmits signals to HMG CoA reductase. We predict that sterol-sensing induces conformational changes in the HMG CoA reductase membrane domain that promotes Insig binding. The second phase of the pathway, Phase II, encompasses the recruitment and action of enzymes that polyubiquitinate HMG CoA reductase, thus targeting it for proteasomal recognition and degradation. Phase III,

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