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TitleScap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing.
Journal, issue, pagesCell, Vol. 184, Issue 14, Page 3689-3701.e22, Year 2021
Publish dateJul 8, 2021
AuthorsDaniel L Kober / Arun Radhakrishnan / Joseph L Goldstein / Michael S Brown / Lindsay D Clark / Xiao-Chen Bai / Daniel M Rosenbaum /
PubMed AbstractThe cholesterol-sensing protein Scap induces cholesterol synthesis by transporting membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) from the endoplasmic ...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.
External linksCell / PubMed:34139175 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 4.6 Å
Structure data

EMDB-23405, PDB-7lkf:
WT Chicken Scap L1-L7 / Fab 4G10 complex focused refinement
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-23406:
Map of WT cScap/Fab complex
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-23407:
Map of full mutant cScap/Fab complex
Method: EM (single particle) / Resolution: 4.6 Å

EMDB-23408, PDB-7lkh:
Chicken Scap D435V L1-L7 domain / Fab complex focused map
Method: EM (single particle) / Resolution: 3.5 Å

Source
  • gallus gallus (chicken)
  • mus musculus (house mouse)
  • Mouse (mice)
KeywordsLIPID BINDING PROTEIN / Cholesterol / SREBP

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