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

Enrichment of Endoplasmic Reticulum with Cholesterol Inhibits Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase-2b Activity in Parallel with Increased Order of Membrane Lipids

“…Cholesterol-mediated regulation of the sterol regulatory element-binding protein pathway involves a conformational change in sterol regulatory element-binding protein cleavage-activating protein (SCAP). In this scenario, sterol specificity data are consistent with a direct sterol-SCAP interaction causing this effect (59,60). Indeed, SCAP contains a consensus "sterol-sensing domain" that likely mediates this interaction (44), although direct sterol binding to this protein has not yet been demonstrated.…”

Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol

“…One possibility is that these compounds directly interact with specific proteins, analogous to cholesterol binding to Scap, 50 oxysterols to Insig, 51 or cyclopamine binding to Smoothened in the Hedgehog pathway. 52 Indeed, Adams et al 53 reported that the antipsychotic amphiphile chlorpromazine mimics cholesterol by binding to Scap. This should theoretically suppress SREBP processing and downregulate lipogenic gene expression.…”

“…However, in keeping with this and other studies, 4,6,7 the cholesterol-mimicking effect of APDs could not be reproduced in intact cells. 53 Another possibility is that amphiphiles exert their effects by altering membrane properties. Thus, Cenedella et al 54 using the enantiomer of U18666A showed comparable effects on cholesterol synthesis and apoptosis as the regular isomer.…”

Cholesterol through the Looking Glass

“…SREBP-2 is the major isoform involved in regulating cholesterol homeostasis. When cholesterol levels in the endoplasmic reticulum (ER) exceed a critical threshold (4), the SREBP cleavage-activating protein, Scap, undergoes a conformational change (5), which assists binding of the tethering protein, Insig (6). This traps SREBP-2 in the ER in its inactive precursor form.…”

“…Thus, Scap mutants that are sterol-resistant in terms of suppressing SREBP-2 processing are also resistant to cholesterolinduction of conformational change (5,6). Conversely, Scap mutants that are trapped in the cholesterol-induced conformation cannot mediate SREBP-2 processing in intact cells (7,8).…”