9pxb

Structural highlights

Function

SCAP_CRIGR Escort protein required for cholesterol as well as lipid homeostasis (PubMed:10497220, PubMed:12482938, PubMed:15728349, PubMed:15899885, PubMed:17428919, PubMed:8898195). Regulates export of the SCAP-SREBP complex from the endoplasmic reticulum to the Golgi upon low cholesterol, thereby regulating the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:10497220, PubMed:12482938, PubMed:15728349, PubMed:15899885, PubMed:17428919, PubMed:27068746, PubMed:8898195). At high sterol concentrations, formation of a ternary complex with INSIG (INSIG1 or INSIG2) leads to mask the ER export signal in SCAP, promoting retention of the complex in the endoplasmic reticulum (PubMed:12482938, PubMed:15728349, PubMed:15899885, PubMed:27068746). Low sterol concentrations trigger release of INSIG, a conformational change in the SSD domain of SCAP, unmasking of the ER export signal, promoting recruitment into COPII-coated vesicles and transport of the SCAP-SREBP to the Golgi: in the Golgi, SREBPs are then processed, releasing the transcription factor fragment of SREBPs from the membrane, its import into the nucleus and up-regulation of LDLR, INSIG1 and the mevalonate pathway (PubMed:15728349, PubMed:15899885, PubMed:17428919, PubMed:27068746). Binds cholesterol via its SSD domain (PubMed:15260976, PubMed:27068746).^{[1] [2] [3] [4] [5] [6] [7] [8]}

References

1. ↑ Rawson RB, DeBose-Boyd R, Goldstein JL, Brown MS. Failure to cleave sterol regulatory element-binding proteins (SREBPs) causes cholesterol auxotrophy in Chinese hamster ovary cells with genetic absence of SREBP cleavage-activating protein. J Biol Chem. 1999 Oct 1;274(40):28549-56. PMID:10497220 doi:10.1074/jbc.274.40.28549
2. ↑ Yabe D, Xia ZP, Adams CM, Rawson RB. Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16672-7. PMID:12482938 doi:10.1073/pnas.262669399
3. ↑ Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol Cell. 2004 Jul 23;15(2):259-68. PMID:15260976 doi:10.1016/j.molcel.2004.06.019
4. ↑ Feramisco JD, Radhakrishnan A, Ikeda Y, Reitz J, Brown MS, Goldstein JL. Intramembrane aspartic acid in SCAP protein governs cholesterol-induced conformational change. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3242-7. PMID:15728349 doi:10.1073/pnas.0500206102
5. ↑ Sun LP, Li L, Goldstein JL, Brown MS. Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. J Biol Chem. 2005 Jul 15;280(28):26483-90. PMID:15899885 doi:10.1074/jbc.M504041200
6. ↑ 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. 2007 Apr 17;104(16):6519-26. PMID:17428919 doi:10.1073/pnas.0700907104
7. ↑ Zhang Y, Lee KM, Kinch LN, Clark L, Grishin NV, Rosenbaum DM, Brown MS, Goldstein JL, Radhakrishnan A. Direct Demonstration That Loop1 of Scap Binds to Loop7: A CRUCIAL EVENT IN CHOLESTEROL HOMEOSTASIS. J Biol Chem. 2016 Jun 10;291(24):12888-12896. PMID:27068746 doi:10.1074/jbc.M116.729798
8. ↑ Hua X, Nohturfft A, Goldstein JL, Brown MS. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell. 1996 Nov 1;87(3):415-26. PMID:8898195 doi:10.1016/s0092-8674(00)81362-8