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A short introduction about HMG-CoA reductase
HMG-CoA reductase or 3-hydroxy-3-methylglutaryl coenzyme-A reductase is an endoplasmic reticulum membrane-bound enzyme. It catalyzes the conversion of HMG-CoA to mevalonate. This step, formation of the mevalonate, is the rate limiting step of the cholesterol biosynthesis as well as the synthesis of nonsterol isoprenoids such as dolichol and farnesyl pyrophosphate. Therefore, HMG-CoA reductase is the first regulatory point of the cholesterol biosynthesis.
There are many types of regulatory mechanisms that control the activity of the HMG-CoA reductase and thereby limit the formation of mevalonate. Among these mechanisms, accelerated degradation of the HMG-CoA reductase from the endoplasmic reticulum membrane is the main one. Accelerated degradation of this enzyme is a type of feedback control initiated by the intracellular signals.
Intracellular accumulated steroids bind to the enzyme and steroid-enzyme complex ultimately binds to the certain types of proteins located in the membrane of endoplasmic reticulum (Insig-1 and Insig-2).
Regulatory mechanism of the HMG-CoA reductase
Binding of the steroid-enzyme complex to the Insig proteins is purely mediated by the membrane domain of the enzyme HMG-CoA reductase which contains eight transmembrane helices. After binding of the steroid-enzyme complex to the Insig proteins, Insig-associated ubiquitin ligase enzymes are activated that facilitate the ubiquitination of the lysine residue located in the membrane domain of the enzyme.
The lysine residue of membrane domain is exposed to the cytosol and the ubiquitination of this lysine residue is a mark that signals the dislocation of the enzyme from the endoplasmic reticulum to the cytosol. The HMG-CoA reductase translocated into the cytoplasm is ultimately degraded via the proteasome.
Another feedback mechanism involved in the HMG-CoA reductase is the steroid induced binding of the Insig proteins to Scap which is another membrane protein of endoplasmic reticulum. Scap is associated with the membrane-bound sterol regulatory element binding proteins (SREBPs) which modulate the transcription of the genes encoding HMG-CoA reductase and other cholesterol biosynthetic enzymes.
When cholesterol is depleted inside the cell, Scap facilitates the transport of SREBPs from the endoplasmic reticulum to the Golgi complex where active fragments of the SREBPs are released from the membrane and migrate to the nucleus where they activate the target genes.
Excess of the intracellular sterols promotes Insig proteins to bind with the Scap proteins. Scap-bound Insig protein complex inhibits the transport of Scap-SREBP complex from the endoplasmic reticulum to the Golgi complex. In the absence of transport, proteolytic activation of the SREBPs doesn’t occur that leads to the expression of SREBP target genes leading to the decline of the cholesterol.
To clarify the accelerated degradative feedback inhibition of the HMG-CoA reductase, researchers took two lines of mice; 1) transgenic mice capable of expressing membrane domain of HMG-CoA reductase in liver (which is necessary for the Insig-mediated and sterol-accelerated degradation) and 2) knockin mice bearing mutations in the endogenous HMG-CoA reductase gene that causes change in the lysine residue at 89 and 248 positions to argentine. These mutations prevent the sterol-induced ubiquitination and subsequent degradation of the HMG-CoA reductase in the cultured cells.