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

• Autores: Ruobing Ren, Xinhui Zhou, Yuan He
• Localización: Science, ISSN 0036-8075, Vol. 349, Nº 6244, 2015, págs. 187-191
• Idioma: inglés
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• Resumen

  • 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.