Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis.

Insig-1 and Insig-2 are closely related proteins of the endoplasmic reticulum (ER) that mediate feedback control of cholesterol synthesis by sterol-dependent binding to the following two membrane proteins: the escort protein Scap, thus preventing proteolytic processing of sterol regulatory element-binding proteins; and the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl CoA reductase, thus ...
inducing the ubiquitination and ER-associated degradation of the enzyme. Here, we report that the conserved Asp-205 in Insig-1, which abuts the fourth transmembrane helix at the cytosolic side of the ER membrane, is essential for its dual function. When Asp-205 was mutated to alanine, the mutant Insig-1 lost the ability to bind to Scap and, thus, was unable to suppress the cleavage of sterol regulatory element-binding proteins. The mutant Insig-1 was ineffective also in accelerating sterol-stimulated degradation of 3-hydroxy-3-methylglutaryl CoA reductase. Alanine substitution of the corresponding aspartic acid in Insig-2 produced the same dual defects. These studies identify a single amino acid residue that is crucial for the function of Insig proteins in regulating cholesterol homeostasis in mammalian cells.
Mesh Terms:
Amino Acid Sequence, Amino Acid Substitution, Animals, Aspartic Acid, Cell Membrane, Cells, Cultured, Cholesterol, Homeostasis, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Molecular Sequence Data, Point Mutation
Proc. Natl. Acad. Sci. U.S.A.
Date: Apr. 18, 2006
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