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,
