PROTEIN STRUCTURE. Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels. Author 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 Publication Year 2015 Type Journal Article 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. Keywords Bacterial Proteins, Humans, Membrane Proteins, Crystallography, X-Ray, Protein Structure, Secondary, Protein Multimerization, Diglycerides, Hydroxycholesterols, Intracellular Signaling Peptides and Proteins, Mycobacterium, Sterol Regulatory Element Binding Proteins Journal Science Volume 349 Issue 6244 Pages 187-91 Date Published 2015 Jul 10 ISSN Number 1095-9203 DOI 10.1126/science.aab1091 Alternate Journal Science PMCID PMC4704858 PMID 26160948 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML