In mammalian cells, the supply of lipids is co-ordinated with demand through the transcriptional control of genes encoding proteins required for synthesis or uptake. The sterol regulatory element binding proteins (SREBPs) are responsible for increased transcription of these genes when lipid level fall. Mammals have three SREBPs (-1a, -1c and -2), which are the products of two distinct genes. Synthesized as approximately 120 kDa precursors, they are inserted into membranes of the endoplasmic reticulum (ER) in a hairpin fashion. Both the N-terminal transcription factor domain and the C-terminal regulatory domain face the cytoplasm. These are connected by two transmembrane helices separated by a short loop projecting into the ER lumen. The C-terminal domain of SREBP interacts with the C-terminal domain of SREBP-cleavage-activating protein (SCAP). The N-terminal half of SCAP contains eight transmembrane helices, five of which (helices 2-6) form the sterol-sensing domain. In response to cellular demand for lipid, this complex exits the ER and transits to the Golgi apparatus, where two distinct proteases cleave the SREBP precursor to release the transcriptionally active N-terminus. This process was the first example of regulated intramembrane proteolysis for which the proteases were identified. Recent work has additionally uncovered integral membrane proteins, insig-1 and insig-2, that are required to retain the SREBP-SCAP complex in the ER in the presence of sterols, thus providing a more complete understanding of the control of proteolysis in this complex regulatory pathway.
Control of lipid metabolism by regulated intramembrane proteolysis of sterol regulatory element binding proteins (SREBPs)
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Jeremy Saklatvala, Hideaki Nagase, Guy Salvesen, Robert B Rawson; Control of lipid metabolism by regulated intramembrane proteolysis of sterol regulatory element binding proteins (SREBPs). Biochem Soc Symp 1 September 2003; 70 221–231. doi: https://doi.org/10.1042/bss0700221
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