HGNC Approved Gene Symbol: SCAP
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38) : 3:47,413,681-47,477,127 (from NCBI)
Studying the molecular defect in a class of sterol-resistant Chinese hamster ovary (CHO) cells, Hua et al. (1996) found that the phenotype was caused by a gain-of-function point mutation in a gene encoding a novel membrane protein which they called SCAP (for 'SREBP cleavage-activating protein'). The mutant SCAP activates cleavage of the sterol regulatory element binding proteins (184756; 600481), and it renders the reaction resistant to suppression by sterols. Although wildtype SCAP can exert the same effect when overexpressed by transfection, the mutant form is much more active. The mutation that activates SCAP in the mutant CHO cells is a G-to-A transition that changes codon 443 from aspartic acid to asparagine. The hamster SCAP gene encodes a 1,276-amino acid polypeptide that is highly homologous to C. elegans D2013.8 (Wilson et al., 1994) and to a human gene (GenBank D83782) designated KIAA0199 by Nagase et al. (1996). The deduced 1,277-amino acid protein contains G-beta repeats found in beta-transducins. Northern blot analysis detected SCAP expression in all tissues examined, with highest expression in kidney and ovary.
By PCR of KIAA0199 and 5-prime RACE of a human hepatoma cell line, Hua et al. (1996) cloned full-length SCAP. They demonstrated that SCAP contains multiple membrane-spanning segments, some of which show a highly significant resemblance to the membrane-spanning segments of HMG CoA reductase (142910), an enzyme whose degradation is regulated by sterols. Hua et al. (1996) stated that SCAP appears to be a central regulator of cholesterol metabolism in animal cells.
Nakajima et al. (1999) cloned a full-length human SCAP cDNA. The deduced protein contains 8 transmembrane regions in the N terminus, followed by a sterol-sensing domain and hydrophilic C-terminal domains containing 4 copies of the WD repeat.
Nakajima et al. (1999) determined that the SCAP gene contains 23 exons and spans over 30 kb. Exon 1 is noncoding. The 5-prime flanking region is G/C rich and contains ADD1/SREBP1 binding sites in addition to SP1 (189906) and AP2 (107580) sites.
Cholesterol homeostasis in animal cells is achieved by regulated cleavage of SREBPs, membrane-bound transcription factors. Proteolytic release of the active domains of SREBPs from membranes requires a sterol-sensing protein called SCAP, which forms a complex with SREBPs. In sterol-depleted cells, DeBose-Boyd et al. (1999) found that SCAP escorts SREBPs from the endoplasmic reticulum (ER) to the Golgi, where SREBPs are cleaved by site-1 protease (S1P; 603355). The authors showed that sterols block this transport and abolish cleavage. Relocating active S1P from Golgi to ER by treating cells with brefeldin A or by fusing the ER retention signal KDEL to S1P obviated the SCAP requirement and rendered cleavage insensitive to sterols. DeBose-Boyd et al. (1999) concluded that transport-dependent proteolysis may be a common mechanism to regulate the processing of membrane proteins.
Nohturfft et al. (2000) reported an in vitro system to measure incorporation of SCAP into ER vesicles. When membranes were isolated from sterol-depleted cells, SCAP entered vesicles in a reaction requiring nucleoside triphosphates and cytosol. SCAP budding was diminished in membranes from sterol-treated cells. Kinetics of induction of budding in vitro matched kinetics of ER exit in living cells expressing green fluorescent protein-SCAP. These data localized the sterol-regulated step to budding of SCAP from ER and provided a system for biochemical dissection.
Brown et al. (2002) showed that addition of cholesterol to ER membranes in vitro caused a conformational change in SCAP, detected by the unmasking of closely spaced trypsin cleavage sites. Two mutant forms of SCAP (tyr298 to cys and asp443 to asn) that were refractory to sterol regulation in vivo were also refractory to sterol-induced conformational change in vitro. A potent regulator of SCAP in vivo, 25-hydroxycholesterol, failed to change the conformation of SCAP in vitro, suggesting that oxysterols act in intact cells by translocating cholesterol from plasma membrane to ER. These studies demonstrated an in vitro effect of cholesterol on the sterol regulatory machinery.
Cao et al. (2002) identified a loss-of-function -11C-T promoter polymorphism in the SCAP gene in 2 unrelated Caucasian subjects ascertained on the basis of a biochemical diagnosis of combined hyperlipidemia (144250). The mutation was absent from normolipidemic subjects across 3 ethnic groups. The -11T allele was associated with a marked reduction in promoter activity in a luciferase-based expression system.
In mice with a conditional SCAP deficiency in liver, Kuriyama et al. (2005) observed that decreased fatty acid synthesis in the liver was balanced by an equal increase in nonhepatic tissues, primarily adipose tissue. This compensatory response was mediated by an insulin-dependent increase in adipocyte SREBP1c (see 184756) and disappeared upon fasting. Adipocytes showed insulin hypersensitivity, and plasma VLDL triglycerides were dramatically reduced in these mice.
By PCR and SSCP analysis of SCAP in 75 Caucasian individuals, Iwaki et al. (1999) identified a common amino acid polymorphism of isoleucine/valine at codon 796 in exon 16. The allelic frequencies were: isoleucine (A) allele, 0.57, and valine (G) allele, 0.43.
By radiation hybrid analysis, Nagase et al. (1996) mapped the SCAP gene to chromosome 3.
Brown, A. J., Sun, L., Feramisco, J. D., Brown, M. S., Goldstein, J. L. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Molec. Cell 10: 237-245, 2002. [PubMed: 12191470] [Full Text: https://doi.org/10.1016/s1097-2765(02)00591-9]
Cao, H., Miskie, B. A., Hegele, R. A. Functional promoter polymorphism in SREBP cleavage-activating protein (SCAP). J. Hum. Genet. 47: 492-496, 2002. [PubMed: 12202990] [Full Text: https://doi.org/10.1007/s100380200072]
DeBose-Boyd, R. A., Brown, M. S., Li, W.-P., Nohturfft, A., Goldstein, J. L., Espenshade, P. J. Transport-dependent proteolysis of SREBP: relocation of Site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 99: 703-712, 1999. [PubMed: 10619424] [Full Text: https://doi.org/10.1016/s0092-8674(00)81668-2]
Hua, X., Nohturfft, A., Goldstein, J. L., Brown, M. S. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87: 415-426, 1996. [PubMed: 8898195] [Full Text: https://doi.org/10.1016/s0092-8674(00)81362-8]
Iwaki, K., Nakajima, T., Ota, N., Emi, M. A common ile796val polymorphism of the human SREBP cleavage-activating protein (SCAP) gene. J. Hum. Genet. 44: 421-422, 1999. [PubMed: 10570919] [Full Text: https://doi.org/10.1007/s100380050193]
Kuriyama, H., Liang, G., Engelking, L. J., Horton, J. D., Goldstein, J. L., Brown, M. S. Compensatory increase in fatty acid synthesis in adipose tissue of mice with conditional deficiency of SCAP in liver. Cell Metab. 1: 41-51, 2005. [PubMed: 16054043] [Full Text: https://doi.org/10.1016/j.cmet.2004.11.004]
Nagase, T., Seki, N., Ishikawa, K., Tanaka, A., Nomura, N. Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161--KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 3: 17-24, 1996. [PubMed: 8724849] [Full Text: https://doi.org/10.1093/dnares/3.1.17]
Nakajima, T., Hamakubo, T., Kodama, T., Inazawa, J., Emi, M. Genomic structure and chromosomal mapping of the human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) gene. J. Hum. Genet. 44: 402-407, 1999. [PubMed: 10570913] [Full Text: https://doi.org/10.1007/s100380050187]
Nohturfft, A., Yabe, D., Goldstein, J. L., Brown, M. S., Espenshade, P. J. Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 102: 315-323, 2000. [PubMed: 10975522] [Full Text: https://doi.org/10.1016/s0092-8674(00)00037-4]
Wilson, R., Ainscough, R., Anderson, K., Baynes, C., Berks, M., Bonfield, J., Burton, J., Connell, M., Copsey, T., Cooper, J., Coulson, A., Craxton, M., and 43 others. 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature 368: 32-38, 1994. [PubMed: 7906398] [Full Text: https://doi.org/10.1038/368032a0]