SREBP cleavage-activating protein explained

Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP, is a protein that in humans is encoded by the SCAP gene.^{[1] [2] [3] [4]}

SCAP contains a sterol-sensing domain (SSD) and seven WD domains. In cholesterol-depleted cells, this protein binds to sterol regulatory element binding proteins (SREBPs) and mediates their transport from the ER to the Golgi apparatus. The SREBPs are then proteolytically cleaved and stimulate sterol biosynthesis.^[1]

Function

SCAP is a regulatory protein that is required for the proteolytic cleavage of the sterol regulatory element-binding protein (SREBP). SCAP is an integral membrane protein located in the endoplasmic reticulum (ER). One of the cytosolic regions of SCAP contains a hexapeptide amino acid sequence, MELADL, that functions to detect cellular cholesterol. When cholesterol is present, SCAP undergoes a conformational change that prevents it from activating SREBP and cholesterol synthesis does not occur.^[5]

Structure

Scap has 8 transmembrane domains and both the N-terminal and C-terminal face the cytoplasm. Also, it binds SREBP by a series of consecutive WD repeats on its C-terminus.^[6]

Further reading

• Le Hellard S, Theisen FM, Haberhausen M, etal . Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects? . Mol. Psychiatry . 14 . 3 . 308–17 . 2009 . 18195716 . 10.1038/sj.mp.4002133 . 28333347 .
• McGeachie M, Ramoni RL, Mychaleckyj JC, etal . Integrative predictive model of coronary artery calcification in atherosclerosis. . Circulation . 120 . 24 . 2448–54 . 2009 . 19948975 . 10.1161/CIRCULATIONAHA.109.865501 . 2810344.
• Friedlander Y, Schwartz SM, Durst R, etal . SREBP-2 and SCAP isoforms and risk of early onset myocardial infarction. . Atherosclerosis . 196 . 2 . 896–904 . 2008 . 17383658 . 10.1016/j.atherosclerosis.2007.02.006 .
• Otsuki T, Ota T, Nishikawa T, etal . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries. . DNA Res. . 12 . 2 . 117–26 . 2005 . 16303743 . 10.1093/dnares/12.2.117 . free .
• Javitt NB . Cholesterol, hydroxycholesterols, and bile acids. . Biochem. Biophys. Res. Commun. . 292 . 5 . 1147–53 . 2002 . 11969205 . 10.1006/bbrc.2001.2013 .
• Kimura K, Wakamatsu A, Suzuki Y, etal . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 10.1101/gr.4039406 . 1356129.
• Lee JN, Gong Y, Zhang X, Ye J . Proteasomal degradation of ubiquitinated Insig proteins is determined by serine residues flanking ubiquitinated lysines. . Proc. Natl. Acad. Sci. U.S.A. . 103 . 13 . 4958–63 . 2006 . 16549805 . 10.1073/pnas.0600422103 . 1405624. 2006PNAS..103.4958L . free .
• Lu Y, Dollé ME, Imholz S. Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations. . J. Lipid Res. . 49 . 12 . 2582–9 . 2008 . 18660489 . 10.1194/jlr.M800232-JLR200 . free . etal.
• Suchanek M, Radzikowska A, Thiele C . Photo-leucine and photo-methionine allow identification of protein-protein interactions in living cells. . Nat. Methods . 2 . 4 . 261–7 . 2005 . 15782218 . 10.1038/nmeth752 . free .
• Irisawa M, Inoue J, Ozawa N, etal . The sterol-sensing endoplasmic reticulum (ER) membrane protein TRC8 hampers ER to Golgi transport of sterol regulatory element-binding protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces SREBP-2 cleavage. . J. Biol. Chem. . 284 . 42 . 28995–9004 . 2009 . 19706601 . 10.1074/jbc.M109.041376 . 2781446 . free .
• Yang LH, Chen DF . [Effects of TNF alpha on the expression of SCAP and triglyceride contents in cultured steatotic hepatocytes] . Zhonghua Gan Zang Bing Za Zhi . 15 . 10 . 767–70 . 2007 . 17963605 .
• Voora D, Shah SH, Reed CR, etal . Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response . Circ Cardiovasc Genet . 1 . 2 . 100–6 . 2008 . 20031551 . 10.1161/CIRCGENETICS.108.795013 . 2995295 .
• Fan YM, Karhunen PJ, Levula M, etal . Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death . Thromb J . 6 . 17 . 2008 . 19116028 . 10.1186/1477-9560-6-17 . 2645360 . free .
• Vasseur F, Caeyseele T, Barat-Houari M, etal . Concordance of two multiple analytical approaches demonstrate that interaction between BMI and ADIPOQ haplotypes is a determinant of LDL cholesterol in a general French population . J. Hum. Genet. . 55 . 4 . 227–31 . 2010 . 20186155 . 10.1038/jhg.2010.10 . free .
• Durst R, Jansen A, Erez G, etal . The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients . Atherosclerosis . 189 . 2 . 443–50 . 2006 . 16466730 . 10.1016/j.atherosclerosis.2006.01.001 .
• Liu X, Li Y, Lu X, etal . Interactions among genetic variants from SREBP2 activating-related pathway on risk of coronary heart disease in Chinese Han population . Atherosclerosis . 208 . 2 . 421–6 . 2010 . 19740467 . 10.1016/j.atherosclerosis.2009.08.011 .
• Chen SN, Cilingiroglu M, Todd J, etal . Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis . BMC Med. Genet. . 10. 111 . 2009 . 19878569 . 10.1186/1471-2350-10-111 . 2775733 . free .
• Lee JN, Zhang X, Feramisco JD, etal . Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step . J. Biol. Chem. . 283 . 48 . 33772–83 . 2008 . 18835813 . 10.1074/jbc.M806108200 . 2586246. free .
• Nieminen T, Matinheikki J, Nenonen A, etal . The relationship of sterol regulatory element-binding protein cleavage-activation protein and apolipoprotein E gene polymorphisms with metabolic changes during weight reduction . Metab. Clin. Exp. . 56 . 7 . 876–80 . 2007 . 17570245 . 10.1016/j.metabol.2007.02.003 .

Notes and References

1. Web site: Entrez Gene: SREBF chaperone.
2. 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 . 1 . 17–24 . February 1996 . 8724849 . 10.1093/dnares/3.1.17. free .
3. Hua X, Nohturfft A, Goldstein JL, Brown MS . Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein . Cell . 87 . 3 . 415–26 . November 1996 . 8898195 . 10.1016/S0092-8674(00)81362-8. 1963192 . free .
4. 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 . 6 . 402–7 . 1999 . 10570913 . 10.1007/s100380050187 . free .
5. Sun LP, Seemann J, Goldstein JL, Brown MS . Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins . Proc. Natl. Acad. Sci. U.S.A. . 104 . 16 . 6519–26 . 2007 . 17428919 . 10.1073/pnas.0700907104 . 1851663 . free .
6. Brown MS, Goldstein JL . A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood . Proc. Natl. Acad. Sci. U.S.A. . 96 . 20 . 11041–8 . 1999 . 10500120 . 10.1073/pnas.96.20.11041 . 34238 . 1999PNAS...9611041B . free .