Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER

Espenshade, Peter J.; Li, Wei Ping; Yabe, Daisuke

doi:10.1073/pnas.182412799

Cited by 135 publications

(99 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both Insig-interacting proteins have a similar organization: 1) an N-terminal polytopic membrane domain containing eight membrane-spanning segments, and 2) a long hydrophilic C-terminal extension that projects into the cytosol. In SCAP, this extension is composed of multiple WD-repeat domains that form propeller-like structures that bind SREBPs (12) and also coat proteins that cluster SCAP/SREBP complexes into CopII vesicles that bud from the ER (25). In HMG CoA reductase, the globular cytosolic domain contains all of the catalytic activity of the enzyme (26,27).…”

Section: Discussionmentioning

confidence: 99%

Membrane Topology of Human Insig-1, a Protein Regulator of Lipid Synthesis

Feramisco¹,

Goldstein

Brown

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Insig-1 is an intrinsic protein of the endoplasmic reticulum (ER) that regulates the proteolytic processing of membrane-bound sterol regulatory element-binding proteins (SREBPs), transcription factors that activate the synthesis of cholesterol and fatty acids in mammalian cells. When cellular levels of sterols rise, Insig-1 binds to the membranous sterol-sensing domain of SREBP cleavage-activating protein (SCAP), retaining the SCAP/SREBP complex in the ER and preventing it from moving to the Golgi for proteolytic processing. Under conditions of sterol excess, Insig-1 also binds to the ER enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, facilitating its ubiquitination and proteasomal degradation. Here, we use protease protection, glycosylation site mapping, and cysteine derivitization to define the topology of the 277-amino acid human Insig-1. The data indicate that short segments at the N and C termini of Insig-1 face the cytosol. Most of the protein is buried within the membrane, forming six transmembrane segments separated by five short luminal and cytosolic loops that range from ϳ5 to 16 amino acids. The membranous nature of Insig-1 is consistent with its sterol-dependent binding to hydrophobic sterolsensing domains in SCAP and HMG CoA reductase.

show abstract

Section: Discussionmentioning

confidence: 99%

Membrane Topology of Human Insig-1, a Protein Regulator of Lipid Synthesis

Feramisco¹,

Goldstein

Brown

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In sterol-depleted cells, the Scap/SREBP complex exits the ER in COPII-coated vesicles that bud from ER membranes (Fig. 2) (Nohturfft et al 2000;Espenshade et al 2002;Sun et al 2005). As a result, SREBPs are cleaved by S1P and S2P in the Golgi complex and the transcription factor domain is released from membranes.…”

Section: Regulation Of the Srebp Pathway In Cultured Cells Regulated mentioning

confidence: 99%

Regulation of Cholesterol and Fatty Acid Synthesis

Jin

DeBose‐Boyd²

2011

Cold Spring Harbor Perspectives in Biology

205

148

View full text Add to dashboard Cite

“…In previous work, the Brown and Goldstein laboratory established a role for COPII proteins in the steroldeprivation-dependent packaging of Scap-SREBP into transport vesicles by using a cell-free vesicle budding reaction that recapitulates the authentic sorting reaction (6,7). Further work identified the sorting signal, MELADL, located near TM domain 6 of the largest cytosolically exposed loop of Scap (8).…”

Section: Sterols and Protein Sorting In The Endoplasmic Reticulummentioning

confidence: 99%

How sterols regulate protein sorting and traffic

Schekman

2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER

Cited by 135 publications

References 26 publications

Membrane Topology of Human Insig-1, a Protein Regulator of Lipid Synthesis

Membrane Topology of Human Insig-1, a Protein Regulator of Lipid Synthesis

Regulation of Cholesterol and Fatty Acid Synthesis

How sterols regulate protein sorting and traffic

Contact Info

Product

Resources

About