Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins.
This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described ... insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. The sequences of human insig-1 and -2 are 59% identical. Both proteins are predicted to contain six transmembrane helices. The proteins differ functionally in two respects: (i) production of insig-1, but not insig-2, in cultured mammalian cells requires nuclear SREBPs; and (ii) at high levels of expression, insig-1, but not insig-2, can block SCAP movement in the absence of exogenous sterols. The combined actions of insig-1 and -2 permit feedback regulation of cholesterol synthesis over a wide range of sterol concentrations.
Mesh Terms:
Amino Acid Sequence, Animals, Blotting, Northern, CCAAT-Enhancer-Binding Proteins, CHO Cells, Carrier Proteins, Cells, Cultured, Cholesterol, Cricetinae, DNA, Complementary, DNA-Binding Proteins, Dose-Response Relationship, Drug, Endoplasmic Reticulum, Golgi Apparatus, Humans, Immunoblotting, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Molecular Sequence Data, Mutation, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Proteins, Sequence Homology, Amino Acid, Sterol Regulatory Element Binding Protein 1, Time Factors, Transcription Factors, Transfection
Amino Acid Sequence, Animals, Blotting, Northern, CCAAT-Enhancer-Binding Proteins, CHO Cells, Carrier Proteins, Cells, Cultured, Cholesterol, Cricetinae, DNA, Complementary, DNA-Binding Proteins, Dose-Response Relationship, Drug, Endoplasmic Reticulum, Golgi Apparatus, Humans, Immunoblotting, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Molecular Sequence Data, Mutation, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Proteins, Sequence Homology, Amino Acid, Sterol Regulatory Element Binding Protein 1, Time Factors, Transcription Factors, Transfection
Proc. Natl. Acad. Sci. U.S.A.
Date: Oct. 01, 2002
PubMed ID: 12242332
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