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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Physicochemical properties of cells and their effects on intrinsically disordered proteins (IDPs).
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Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain.
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Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes
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Condensed complexes of cholesterol and phospholipids.
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References
More filters
Journal ArticleDOI
A simple method for displaying the hydropathic character of a protein
Jack Kyte,Russell F. Doolittle +1 more
TL;DR: A computer program that progressively evaluates the hydrophilicity and hydrophobicity of a protein along its amino acid sequence has been devised and its simplicity and its graphic nature make it a very useful tool for the evaluation of protein structures.
Journal ArticleDOI
Functional rafts in cell membranes
Kai Simons,Elina Ikonen +1 more
TL;DR: A new aspect of cell membrane structure is presented, based on the dynamic clustering of sphingolipids and cholesterol to form rafts that move within the fluid bilayer that function as platforms for the attachment of proteins when membranes are moved around inside the cell and during signal transduction.
Journal ArticleDOI
The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor
TL;DR: This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.
Journal ArticleDOI
The Caveolae Membrane System
TL;DR: Caveolae constitute an entire membrane system with multiple functions essential for the cell and are capable of importing molecules and delivering them to specific locations within the cell, exporting molecules to extracellular space, and compartmentalizing a variety of signaling activities.
Journal ArticleDOI
Molecular cloning and expression of brain-derived neurotrophic factor.
Joachim Leibrock,Friedrich Lottspeich,Hohn Andreas,Magdalena Hofer,Bastian Hengerer,Piotr Masiakowski,Hans Thoenen,Yves-Alain Barde +7 more
TL;DR: The full primary structure of brain-derived neurotrophic factor is reported and it is established that these two neurotrophic factors are related both functionally and structurally.