Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3689-3701.e22
JournalCell
Volume184
Issue number14
DOIs
StatePublished - Jul 8 2021

Keywords

  • Golgi apparatus
  • Insig
  • SREBP
  • Scap
  • cholesterol
  • cryo-electron microscopy
  • endoplasmic reticulum
  • lipid metabolism
  • membrane homeostasis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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