دورية أكاديمية
Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing.
| العنوان: | Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing. |
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| المؤلفون: | Kober DL; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Radhakrishnan A; Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: arun.radhakrishnan@utsouthwestern.edu., Goldstein JL; Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Brown MS; Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Clark LD; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Bai XC; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: xiaochen.bai@utsouthwestern.edu., Rosenbaum DM; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: dan.rosenbaum@utsouthwestern.edu. |
| المصدر: | Cell [Cell] 2021 Jul 08; Vol. 184 (14), pp. 3689-3701.e22. Date of Electronic Publication: 2021 Jun 16. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Cambridge, Ma : Cell Press Original Publication: Cambridge, MIT Press. |
| مواضيع طبية MeSH: | Cholesterol/*metabolism , Membrane Proteins/*chemistry , Membrane Proteins/*metabolism, Amino Acid Sequence ; Animals ; Antibodies/metabolism ; Chickens ; Membrane Proteins/isolation & purification ; Membrane Proteins/ultrastructure ; Models, Biological ; Models, Molecular ; Protein Binding ; Protein Domains ; Protein Structure, Secondary ; Structure-Activity Relationship |
| مستخلص: | The cholesterol-sensing protein Scap induces cholesterol synthesis by transporting membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum (ER) to the Golgi apparatus for proteolytic activation. Transport requires interaction between Scap's two ER luminal loops (L1 and L7), which flank an intramembrane sterol-sensing domain (SSD). Cholesterol inhibits Scap transport by binding to L1, which triggers Scap's binding to Insig, an ER retention protein. Here we used cryoelectron microscopy (cryo-EM) to elucidate two structures of full-length chicken Scap: (1) a wild-type free of Insigs and (2) mutant Scap bound to chicken Insig without cholesterol. Strikingly, L1 and L7 intertwine tightly to form a globular domain that acts as a luminal platform connecting the SSD to the rest of Scap. In the presence of Insig, this platform undergoes a large rotation accompanied by rearrangement of Scap's transmembrane helices. We postulate that this conformational change halts Scap transport of SREBPs and inhibits cholesterol synthesis. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | P01 HL020948 United States HL NHLBI NIH HHS; P30 DK127984 United States DK NIDDK NIH HHS; P01 HL160487 United States HL NHLBI NIH HHS; R35 GM136387 United States GM NIGMS NIH HHS; R01 GM136976 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: Golgi apparatus; Insig; SREBP; Scap; cholesterol; cryo-electron microscopy; endoplasmic reticulum; lipid metabolism; membrane homeostasis |
| المشرفين على المادة: | 0 (Antibodies) 0 (Membrane Proteins) 97C5T2UQ7J (Cholesterol) |
| تواريخ الأحداث: | Date Created: 20210617 Date Completed: 20220103 Latest Revision: 20240315 |
| رمز التحديث: | 20240315 |
| مُعرف محوري في PubMed: | PMC8277531 |
| DOI: | 10.1016/j.cell.2021.05.019 |
| PMID: | 34139175 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1097-4172 |
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| DOI: | 10.1016/j.cell.2021.05.019 |