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

Renhong Yan, Pingping Cao, Wenqi Song, Hongwu Qian, Ximing Du, Hudson W. Coates, Xin Zhao, Yaning Li, Shuai Gao, Xin Gong, Ximing Liu, Jianhua Sui, Jianlin Lei, Hongyuan Yang, Andrew J. Brown, Qiang Zhou, Chuangye Yan, Nieng Yan

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Article numbereabb2224
JournalScience
Volume371
Issue number6533
DOIs
StatePublished - Mar 5 2021

All Science Journal Classification (ASJC) codes

  • General

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