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Overexpression of membrane domain of SCAP prevents sterols from inhibiting SCAPcntdotSREBP exit from endoplasmic reticulum



Overexpression of membrane domain of SCAP prevents sterols from inhibiting SCAPcntdotSREBP exit from endoplasmic reticulum



Journal of Biological Chemistry 275(38): 29881-29886, September 22



SCAP (SREBP cleavage-activating protein) forms a complex with sterol regulatory element-binding proteins (SREBPs) and escorts them from the endoplasmic reticulum (ER) to the Golgi complex where proteases release transcriptionally active segments of SREBPs, which enter the nucleus to activate lipid synthesis. The NH2-terminal segment of SCAP contains eight transmembrane helices, five of which (TM2-6) comprise the sterol-sensing domain. This domain responds to sterols by causing the SCAPcntdotSREBP complex to be retained in the ER, preventing proteolytic release and reducing transcription of lipogenic genes. Here, we use transfection techniques to overexpress a segment of SCAP containing transmembrane helices 1-6 in hamster and human cells. This segment does not interfere with SCAPcntdotSREBP movement to the Golgi in the absence of sterols, but it prevents sterols from suppressing this movement. This block is abolished when SCAP(TM1-6) contains a point mutation (Y298C) that is known to abolish the activity of the sterol-sensing domain. We interpret these findings to indicate that sterols cause the SCAPcntdotSREBP complex to bind to an ER retention protein through an interaction that involves the sterol-sensing domain. The SCAP(TM1-6) segment competes with the SCAPcntdotSREBP complex for binding to this putative retention protein, thereby liberating the SCAPcntdotSREBP complex so that it can move to the Golgi despite the presence of sterols. These studies provide a potential mechanistic explanation for the ability of sterols to block SCAPcntdotSREBP movement from the ER and thereby to control lipid synthesis in animal cells.

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Accession: 011104891

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