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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Inhibition of Protein Translocation across the Endoplasmic Reticulum Membrane by Sterols
IngMarie Nilsson,IngMarie Nilsson,Henna Ohvo-Rekilä,J. Peter Slotte,Arthur E. Johnson,Gunnar von Heijne +5 more
TL;DR: This work reports that an early step in protein translocation across the endoplasmic reticulum (ER) membrane is reversibly inhibited by cholesterol levels significantly lower than those found in the plasma membrane, and shows that high cholesterol levels prevent cross-linking between ribosome-nascent chain complexes and components of the Sec61 translocon, but have no effect on cross-link to the signal recognition particle.
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Expansion of type II CAAX proteases reveals evolutionary origin of γ-secretase subunit APH-1.
TL;DR: Remote similarity between APH-1 and membrane proteases sheds light on APh-1's evolutionary origin and raises the possibility that APH -1 may possess proteolytic activity in the current or ancestral form of γ-secretase.
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Molecular basis of alcoholic fatty liver disease: From incidence to treatment
TL;DR: The importance of research on alcoholic steatosis based on incidence data, key pathogenic mechanisms and therapeutic interventions, and discusses perspectives on the progression of this disease are emphasized.
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Assembly of high density lipoprotein by the ABCA1/apolipoprotein pathway.
TL;DR: Mammalian somatic cells do not catabolize cholesterol and therefore need to export it for sterol homeostasis at the levels of cells and whole bodies, and ABCA1 is a rate-limiting factor of HDL assembly and is regulated by transcriptional factors and posttranscriptional factors.
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Development of an assay for the intermembrane transfer of cholesterol by Niemann-Pick C2 protein.
Jonathan O. Babalola,Michaela Wendeler,Bernadette Breiden,Christoph Arenz,Guenter Schwarzmann,Silvia Locatelli-Hoops,Konrad Sandhoff +6 more
TL;DR: A cell-free assay for measuring intermembrane lipid transport and identifying for the first time the ability of other lysosomal proteins, most notably the GM2-activator protein, to mediate inter Membrane cholesterol transfer are identified.
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