2. Academic Validation
  3. Structural basis for sterol sensing by Scap and Insig

Structural basis for sterol sensing by Scap and Insig

  • Cell Rep. 2021 Jun 29;35(13):109299. doi: 10.1016/j.celrep.2021.109299.
Renhong Yan 1,  Pingping Cao 2,  Wenqi Song 2,  Yaning Li 2,  Tongtong Wang 2,  Hongwu Qian 3,  Chuangye Yan 4,  Nieng Yan 5
Affiliations

Affiliations

  • 1 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China; Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China. Electronic address: yanrenhong@westlake.edu.cn.
  • 2 State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 3 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 4 State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: yancy2019@tsinghua.edu.cn.
  • 5 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: nyan@princeton.edu.
PMID: 34192549 DOI: 10.1016/j.celrep.2021.109299
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.

Keywords

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

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