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

14 Scopus citations

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
Publication statusPublished - Jul 10 2015

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ASJC Scopus subject areas

  • General
  • Medicine(all)

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