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Cholesterol Feedback: A Tale of Two Membrane Proteins and Two Sterol Sensors.
Author(s) -
Brown Michael S.,
Goldstein Joseph L.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.95.2
Subject(s) - golgi apparatus , sterol regulatory element binding protein , endoplasmic reticulum , sterol , biochemistry , microbiology and biotechnology , membrane protein , golgi membrane , proteases , membrane , chemistry , transcription factor , biology , cholesterol , gene , enzyme
Cholesterol is an essential component of animal cell membranes, and its concentration is tightly controlled by a feedback system that operates primarily at the transcriptional level. The feedback system consists of a pair of membrane‐bound proteins, Scap and Insig, that directly bind sterols and sense their concentrations in the membranes of the endoplasmic reticulum (ER). When sterol levels are low, Scap exists in a conformation that allows it to transport membrane‐bound SREBPs from the ER to the Golgi. In the Golgi, sequential proteolysis of SREBP by two membrane‐bound proteases releases the N‐terminal half of the SREBP, allowing its entry into the nucleus where it functions as a transcription factor, activating the genes encoding proteins involved in the synthesis and uptake of cholesterol. When excess sterols build up in ER membranes, Scap binds cholesterol and Insig binds oxysterols. As a result of these binding events, both Scap and Insig undergo conformation changes that result in a series of molecular events that block Scap's ability to transport SREBPs to the Golgi, thus terminating cholesterol synthesis and uptake.