Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels

Ruobing Ren, Xinhui Zhou, Yuan He, Meng Ke, Jianping Wu, Xiaohui Liu, Chuangye Yan, Yixuan Wu, Xin Gong, Xiaoguang Lei, S. Frank Yan, Arun Radhakrishnan, Nieng Yan

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane-embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human Insig-2, together with biochemical characterizations, suggest that the central cavity of Insig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element-binding protein pathway.

Original languageEnglish (US)
Pages (from-to)187-191
Number of pages5
JournalScience
Volume349
Issue number6244
DOIs
StatePublished - Jul 10 2015

Fingerprint

Sterols
Sterol Regulatory Element Binding Proteins
Structural Models
Diglycerides
Protein Subunits
Mycobacterium
Endoplasmic Reticulum
Insulin
Membranes
Genes
Proteins
25-hydroxycholesterol

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels. / Ren, Ruobing; Zhou, Xinhui; He, Yuan; Ke, Meng; Wu, Jianping; Liu, Xiaohui; Yan, Chuangye; Wu, Yixuan; Gong, Xin; Lei, Xiaoguang; Yan, S. Frank; Radhakrishnan, Arun; Yan, Nieng.

In: Science, Vol. 349, No. 6244, 10.07.2015, p. 187-191.

Research output: Contribution to journalArticle

Ren, R, Zhou, X, He, Y, Ke, M, Wu, J, Liu, X, Yan, C, Wu, Y, Gong, X, Lei, X, Yan, SF, Radhakrishnan, A & Yan, N 2015, 'Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels', Science, vol. 349, no. 6244, pp. 187-191. https://doi.org/10.1126/science.aab1091
Ren, Ruobing ; Zhou, Xinhui ; He, Yuan ; Ke, Meng ; Wu, Jianping ; Liu, Xiaohui ; Yan, Chuangye ; Wu, Yixuan ; Gong, Xin ; Lei, Xiaoguang ; Yan, S. Frank ; Radhakrishnan, Arun ; Yan, Nieng. / Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels. In: Science. 2015 ; Vol. 349, No. 6244. pp. 187-191.
@article{9bbebddf257342349f3697b7f2b15401,
title = "Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels",
abstract = "Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane-embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human Insig-2, together with biochemical characterizations, suggest that the central cavity of Insig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element-binding protein pathway.",
author = "Ruobing Ren and Xinhui Zhou and Yuan He and Meng Ke and Jianping Wu and Xiaohui Liu and Chuangye Yan and Yixuan Wu and Xin Gong and Xiaoguang Lei and Yan, {S. Frank} and Arun Radhakrishnan and Nieng Yan",
year = "2015",
month = "7",
day = "10",
doi = "10.1126/science.aab1091",
language = "English (US)",
volume = "349",
pages = "187--191",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6244",

}

TY - JOUR

T1 - Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels

AU - Ren, Ruobing

AU - Zhou, Xinhui

AU - He, Yuan

AU - Ke, Meng

AU - Wu, Jianping

AU - Liu, Xiaohui

AU - Yan, Chuangye

AU - Wu, Yixuan

AU - Gong, Xin

AU - Lei, Xiaoguang

AU - Yan, S. Frank

AU - Radhakrishnan, Arun

AU - Yan, Nieng

PY - 2015/7/10

Y1 - 2015/7/10

N2 - Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane-embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human Insig-2, together with biochemical characterizations, suggest that the central cavity of Insig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element-binding protein pathway.

AB - Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane-embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human Insig-2, together with biochemical characterizations, suggest that the central cavity of Insig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element-binding protein pathway.

UR - http://www.scopus.com/inward/record.url?scp=84937558798&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937558798&partnerID=8YFLogxK

U2 - 10.1126/science.aab1091

DO - 10.1126/science.aab1091

M3 - Article

C2 - 26160948

AN - SCOPUS:84937558798

VL - 349

SP - 187

EP - 191

JO - Science

JF - Science

SN - 0036-8075

IS - 6244

ER -