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sterol regulatory element-binding protein cleavage-activating protein; SREBP cleavage-activating protein; SCAP (SCAP, KIAA0199, PSEC0227)
Function:
- escort protein required for cholesterol as well as lipid homeostasis
- functions to retain SREBPs in the endoplasmic reticulum in the presence of sterols & escort them to the GOLGI in the absence of sterols; this presumably allows close monitoring & response to fluctuations in membrane bilayer sterols
- regulates export of the SCAP/SREBF complex from the ER upon low cholesterol
- formation of a ternary complex with INSIG at high sterol concentrations leads to masking of an ER-export signal in SCAP & retention of the complex in the ER
- low sterol concentrations trigger release of INSIG, a conformational change in the SSC domain of SCAP, unmasking the ER export signal, recruitment into COPII-coated vesicles, transport to the Golgi complex, proteolytic cleavage of SREBF in the Golgi, release of the transcription factor fragment of SREBF from the membrane, its import into the nucleus & up-regulation of LDLR, INSIG1 & the mevalonate pathway (putative)
- forms a stable complex with SREBF1/SREBP1 or SREBF2/SREBP2 through its C-terminal cytoplasmic domain for ER anchoring
- forms a ternary complex with INSIG1 or INSIG2 through its transmembrane domains at high sterol concentrations
- interacts with the SEC23/SEC24 complex (SAR1-GTP-dependent) through an ER export signal in its 3rd cytoplasmic loop
- binds cholesterol through its SSC domain (putative)
Structure:
- membrane region forms a homotetramer
- cholesterol bound to SSC domain of SCAP or oxysterol bound to INSIG1/2 leads to masking of an ER export signal on SCAP possibly by moving the signal further away from ER membrane
- belongs to the WD repeat SCAP family
- contains 1 SSD (sterol-sensing) domain
- contains 7 WD repeats
Compartment:
- multi-pass membrane protein
- endoplasmic reticulum membrane
- Golgi membrane
- cytoplasmic vesicle, COPII- coated vesicle membrane
- moves from the endoplasmic reticulum to the Golgi in the absence of sterols (putative)
Alternative splicing: named isoforms=4
Expression:
- induced by androgen-bound AR & glucocorticoid-bound NR3C1 in a prostate cancer cell line (LNCaP)
Related
sterol regulatory element binding protein (SREBP)
General
glycoprotein
phosphoprotein
transmembrane 8 protein
WD repeat protein family
Properties
SIZE: MW = 140 kD
entity length = 1278 aa
COMPARTMENT: golgi
endoplasmic reticulum
MOTIF: cytoplasmic domain {1-18}
transmembrane domain {19-39}
exoplasmic loop {40-279}
MOTIF: N-glycosylation site {N263}
transmembrane domain {280-300}
cytoplasmic loop {301-312}
transmembrane domain {313-333}
exoplasmic loop {334-344}
transmembrane domain {345-365}
cytoplasmic loop {366-401}
transmembrane domain {402-422}
exoplasmic loop {423-423}
transmembrane domain {424-444}
cytoplasmic loop {445-518}
transmembrane domain {519-539}
exoplasmic loop {540-709}
MOTIF: N-glycosylation site {N590}
N-glycosylation site {N641}
transmembrane domain {710-730}
MOTIF: leucine residue {722-729} (6)
cytoplasmic domain {731-1278}
MOTIF: arginine residue {747-750} (4)
WD repeat {771-811}
proline residue {860-863} (4)
WD repeat {951-1001}
WD repeat {1004-1041}
WD repeat {1076-1113}
WD repeat {1116-1154}
WD repeat {1157-1194}
WD repeat {1196-1234}
Database Correlations
OMIM 601510
UniProt Q12770
Pfam PF00400
Entrez Gene 22937
Kegg hsa:22937
References
- UniProt :accession Q12770
- Janowskii et al,
The hypocholesterolemic agent LY295427 reverses suppression of
sterol regulatory element-binding protein processing mediated
by oxysterols.
J Biol Chem 276:45408, 2001
PMID: 11577112
- Osborne T.
CREating a SACP-less liver keeps SREBPs pinned in the ER
membrane and prevents increased lipid synthesis in response
to low cholesterol and high insulin.
Genes & Develop 15:1873, 2001
PMID: 11485982