2. Academic Validation
  3. PROTEIN STRUCTURE. Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels

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

  • Science. 2015 Jul 10;349(6244):187-91. doi: 10.1126/science.aab1091.
Ruobing Ren 1,  Xinhui Zhou 1,  Yuan He 1,  Meng Ke 1,  Jianping Wu 1,  Xiaohui Liu 2,  Chuangye Yan 1,  Yixuan Wu 1,  Xin Gong 1,  Xiaoguang Lei 2,  S Frank Yan 3,  Arun Radhakrishnan 4,  Nieng Yan 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China. Center for Structural Biology, School of Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
  • 2 National Institute of Biological Sciences, Beijing 102206, China.
  • 3 Molecular Design and Chemical Biology, Therapeutic Modalities, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai 201203, China.
  • 4 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
PMID: 26160948 DOI: 10.1126/science.aab1091
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.

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