2024年3月29日 星期五

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

Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane-embedded sterolsensors 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 Insighomolog 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.

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, 349(6244):187-191.