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

77 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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@article{845c5fe0323342a390899116cfb3236e,

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",

year = "2021",

month = mar,

day = "5",

doi = "10.1126/science.abb2224",

language = "English (US)",

volume = "371",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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TY - JOUR

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.

UR - https://www.scopus.com/pages/publications/85102200251

UR - https://www.scopus.com/pages/publications/85102200251#tab=citedBy

U2 - 10.1126/science.abb2224

DO - 10.1126/science.abb2224

M3 - Article

C2 - 33446483

AN - SCOPUS:85102200251

SN - 0036-8075

VL - 371

JO - Science

JF - Science

IS - 6533

M1 - eabb2224

ER -

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

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