A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols

  • Science. 2021 Mar 5;371(6533):eabb2224. doi: 10.1126/science.abb2224.
Renhong Yan   #  1  2 ,  Pingping Cao   #  3 ,  Wenqi Song   #  3 ,  Hongwu Qian  4 ,  Ximing Du  5 ,  Hudson W Coates  5 ,  Xin Zhao  3 ,  Yaning Li  3 ,  Shuai Gao  4 ,  Xin Gong  6 ,  Ximing Liu  7 ,  Jianhua Sui  7  8 ,  Jianlin Lei  9 ,  Hongyuan Yang  5 ,  Andrew J Brown  5 ,  Qiang Zhou  1  2 ,  Chuangye Yan  10 ,  Nieng Yan  11
Affiliations
  • 1. Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China.
  • 2. Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang Province, China.
  • 3. 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.
  • 4. Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 5. School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW 2052, Australia.
  • 6. Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 7. National Institute of Biological Sciences (NIBS), Beijing 102206, China.
  • 8. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
  • 9. Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 10. 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. [email protected] [email protected].
  • 11. Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. [email protected] [email protected].
  • # Contributed equally.
PMID: 33446483 DOI: 10.1126/science.abb2224
Abstract

The sterol regulatory element-binding protein (SREBP) pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1 and -2, are membrane-embedded sterol sensors. The 25-hydroxycholesterol (25HC)-dependent association of Scap and Insig acts as the master switch for the SREBP pathway. Here, we present cryo-electron microscopy analysis of the human Scap and Insig-2 complex in the presence of 25HC, with the transmembrane (TM) domains determined at an average resolution of 3.7 angstrom. The sterol-sensing domain in Scap and all six TMs in Insig-2 were resolved. A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. Unwinding of the middle of the Scap-S4 segment is crucial for 25HC binding and Insig association.

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