Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles

Christopher M Adams; Joseph L Goldstein; Michael S Brown

doi:10.1073/pnas.1534833100

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Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles

Journal article

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Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles

Christopher M Adams, Joseph L Goldstein and Michael S Brown

Proceedings of the National Academy of Sciences - PNAS, Vol.100(19), pp.10647-10652

09/16/2003

DOI: 10.1073/pnas.1534833100

PMCID: PMC196858

PMID: 12963821

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Abstract

Sterols mediate feedback inhibition of the sterol regulatory element-binding protein (SREBP) pathway by preventing movement of the SREBP cleavage-activating protein (SCAP)/SREBP complex from endoplasmic reticulum (ER) to Golgi, where proteolytic cleavage of SREBPs releases the transcription factor domain that activates genes for lipid biosynthesis. Our laboratory previously used a trypsin cleavage assay to show that the conformation of SCAP is altered in vitro by addition of cholesterol to ER membranes. More recently, Insig-1 and Insig-2 were identified as ER resident proteins that bind the SCAP/SREBP complex and promote its ER retention when cells are treated with sterols. Here, we use the trypsin assay to show that Insig proteins reduce the concentration of cholesterol needed in vitro to produce the conformational change in SCAP. Insig-1 and Insig-2 also enhance the conformational change in SCAP that occurs upon addition of certain cationic amphiphiles, such as chlorpromazine, trifluoperazine, and imipramine, which mimic the effect of cholesterol. The effects of cationic amphiphiles raise the possibility that SCAP may monitor specifically the composition of the cytoplasmic leaflet of the ER membrane.

Carrier Proteins - physiology

Proteins - physiology

Cricetinae

Molecular Mimicry

Animals

Membrane Proteins - physiology

Cholesterol - physiology

Intracellular Signaling Peptides and Proteins

Protein Conformation

CHO Cells

Details

Title: Subtitle: Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles
Creators: Christopher M Adams - Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
Joseph L Goldstein
Michael S Brown
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.100(19), pp.10647-10652
DOI: 10.1073/pnas.1534833100
PMID: 12963821
PMCID: PMC196858
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: P01 HL020948 / NHLBI NIH HHS HL-20948 / NHLBI NIH HHS
Language: English
Date published: 09/16/2003
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984025570502771

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