A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
TLDR
These regulated proteolytic cleavage reactions are ultimately responsible for controlling the level of cholesterol in membranes, cells, and blood.Abstract:
The integrity of cell membranes is maintained by a balance between the amount of cholesterol and the amounts of unsaturated and saturated fatty acids in phospholipids. This balance is maintained by membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) that activate genes encoding enzymes of cholesterol and fatty acid biosynthesis. To enhance transcription, the active NH2-terminal domains of SREBPs are released from endoplasmic reticulum membranes by two sequential cleavages. The first is catalyzed by Site-1 protease (S1P), a membrane-bound subtilisin-related serine protease that cleaves the hydrophilic loop of SREBP that projects into the endoplasmic reticulum lumen. The second cleavage, at Site-2, requires the action of S2P, a hydrophobic protein that appears to be a zinc metalloprotease. This cleavage is unusual because it occurs within a membrane-spanning domain of SREBP. Sterols block SREBP processing by inhibiting S1P. This response is mediated by SREBP cleavage-activating protein (SCAP), a regulatory protein that activates S1P and also serves as a sterol sensor, losing its activity when sterols overaccumulate in cells. These regulated proteolytic cleavage reactions are ultimately responsible for controlling the level of cholesterol in membranes, cells, and blood.read more
Citations
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A new player in the orchestra of cell growth: SREBP activity is regulated by mTORC1 and contributes to the regulation of cell and organ size
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Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia.
André R. Miserez,Patrick Y. Muller,Luca Barella,Sandra Barella,Hannes B. Staehelin,Eran Leitersdorf,Jeremy D. Kark,Yechiel Friedlander +7 more
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Young-Kyo Seo,Hansook Kim Chong,Aniello M. Infante,Seung Soon Im,Xiaohui Xie,Timothy F. Osborne +5 more
TL;DR: Targets of SREBP-1 in mammalian liver are identified using chromatin immunoprecipitation–high-throughput DNA sequencing and it is revealed that an Sp1 consensus site is present as a “coregulatory” motif in 50% of the SRE BP-1 binding peaks, consistent with previous functional studies.
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