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
More filters
Journal ArticleDOI
The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation
Peter Walter,David Ron +1 more
TL;DR: The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum, where they fold and assemble, and only properly assembled proteins advance from the ER to the cell surface.
Journal ArticleDOI
Atherosclerosis: The Road Ahead
TL;DR: Elevated levels of serum cholesterol are probably unique through the hepatic LDL receptor pathway, as evi-in being sufficient to drive the development of athero-denced by the fact that lack of functional LDL receptors sclerosis in humans and experimental animals, even in is responsible for the massive accumulation of LDL in the absence of other known risk factors.
Journal ArticleDOI
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
Marianne Abifadel,Mathilde Varret,Jean-Pierre Rabès,Delphine Allard,Khadija Ouguerram,Martine Devillers,Corinne Cruaud,Suzanne Benjannet,Louise Wickham,D. Erlich,Aurélie Derré,Ludovic Villéger,Michel Farnier,Isabel Beucler,Eric Bruckert,Jean Chambaz,Bernard Chanu,Jean-Michel Lecerf,Gérald Luc,Philippe Moulin,Jean Weissenbach,Annick Prat,Michel Krempf,Claudine Junien,Nabil G. Seidah,Catherine Boileau +25 more
TL;DR: Two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH are reported, a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.
Journal ArticleDOI
Store-operated calcium channels.
Anant B. Parekh,James W. Putney +1 more
TL;DR: The key electrophysiological features of I(CRAC) and other store-operated Ca(2+) currents and how they are regulated are described, and recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca( 2+) entry pathway are considered.
Journal ArticleDOI
Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ
Joyce J. Repa,Guosheng Liang,Jiafu Ou,Yuriy Bashmakov,Jean-Marc A. Lobaccaro,Iichiro Shimomura,Bei Shan,Michael S. Brown,Joseph L. Goldstein,David J. Mangelsdorf +9 more
TL;DR: A novel LXR target is described, the sterol regulatory element-binding protein-1c gene (SREBP-1C), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family and reveals a unique regulatory interplay between cholesterol and fatty acid metabolism.
References
More filters
Journal ArticleDOI
Identification of Complexes between the COOH-terminal Domains of Sterol Regulatory Element-binding Proteins (SREBPs) and SREBP Cleavage-Activating Protein
TL;DR: It is concluded that proteolytic cleavage of SREBPs requires the formation of a complex with the COOH-terminal domain of SCAP and that SCAP is therefore a required element in the regulation of sterol and fatty acid metabolism in animal cells.
Journal ArticleDOI
Differential Stimulation of Cholesterol and Unsaturated Fatty Acid Biosynthesis in Cells Expressing Individual Nuclear Sterol Regulatory Element-binding Proteins
TL;DR: The current data support the emerging view that the nSREBPs act in complementary ways to modulate the lipid composition of cell membranes.
Journal ArticleDOI
Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies.
TL;DR: Data from an in vivo competition assay in transfected cells are interpreted to indicate that the SREBP·SCAP complex directs the Site-1 protease to its target in the lumenal domain of SRE BP and that disruption of this complex inactivates the Sites-1 cleavage reaction.
Journal ArticleDOI
Chromatin, TAFs, and a novel multiprotein coactivator are required for synergistic activation by Sp1 and SREBP-1a in vitro
Anders M. Näär,Pierre A. Beaurang,Karen M. Robinson,Jonathan D. Oliner,Daina Avizonis,Sigrid Scheek,Jörk Zwicker,James T. Kadonaga,Robert Tjian +8 more
TL;DR: The development of a reconstituted chromatin transcription system has allowed us to isolate a novel coactivator that is recruited by the SREBP-1a activation domain and that functions in concert with TFIID to coordinate the action of multiple activators at complex promoters in the context of chromatin.
Journal ArticleDOI
Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain.
TL;DR: The membrane-spanning domains of SCAP and HMG-CoA reductase confer sterol sensitivity upon the functional activities of the two molecules, consistent with the notion that sterols regulate both proteins by a common mechanism.