Structural basis for sterol sensing by Scap and Insig

Renhong Yan, Pingping Cao, Wenqi Song, Yaning Li, Tongtong Wang, Hongwu Qian, Chuangye Yan, Nieng Yan

Research output: Contribution to journalArticlepeer-review

Abstract

The sterol regulatory element-binding protein (SREBP) pathway monitors the cellular cholesterol level through sterol-regulated association between the SREBP cleavage-activating protein (Scap) and the insulin-induced gene (Insig). Despite structural determination of the Scap and Insig-2 complex bound to 25-hydroxycholesterol, the luminal domains of Scap remain unresolved. In this study, combining cryogenic electron microscopy (cryo-EM) analysis and artificial intelligence-facilitated structural prediction, we report the structure of the human Scap/Insig-2 complex purified in digitonin. The luminal domain loop 1 and a co-folded segment in loop 7 of Scap resemble those of the luminal/extracellular domain in NPC1 and related proteins, providing clues to the cholesterol-regulated interaction of loop 1 and loop 7. An additional luminal interface is observed between Scap and Insig. We also show that Scap(D428A), which inhibits SREBP activation even under sterol depletion, exhibits an identical conformation with the wild-type protein when complexed with Insig-2, and its constitutive suppression of the SREBP pathway may also involve a later step in protein trafficking.

Original languageEnglish (US)
Article number109299
JournalCell Reports
Volume35
Issue number13
DOIs
StatePublished - Jun 29 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • cholesterol metabolism
  • cryo-EM structure
  • Insig
  • Loop 1
  • Loop 7
  • Scap
  • SREBP pathway
  • sterol sensing domain

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