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

doi:10.1126/science.abb2224

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 journal › Article › peer-review

48 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 language	English (US)
Article number	eabb2224
Journal	Science
Volume	371
Issue number	6533
DOIs	https://doi.org/10.1126/science.abb2224
State	Published - Mar 5 2021

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

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.",

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

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doi = "10.1126/science.abb2224",

language = "English (US)",

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journal = "Science",

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T1 - A structure of human scap bound to insig-2 suggests how their interaction is regulated by sterols

AU - Yan, Renhong

AU - Cao, Pingping

AU - Song, Wenqi

AU - Qian, Hongwu

AU - Du, Ximing

AU - Coates, Hudson W.

AU - Zhao, Xin

AU - Li, Yaning

AU - Gao, Shuai

AU - Gong, Xin

AU - Liu, Ximing

AU - Sui, Jianhua

AU - Lei, Jianlin

AU - Yang, Hongyuan

AU - Brown, Andrew J.

AU - Zhou, Qiang

AU - Yan, Chuangye

AU - Yan, Nieng

PY - 2021/3/5

Y1 - 2021/3/5

N2 - 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.

AB - 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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DO - 10.1126/science.abb2224

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

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