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

TitlePROTEIN STRUCTURE. Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels.
Publication TypeJournal Article
Year of Publication2015
AuthorsRen, R, Zhou, X, He, Y, Ke, M, Wu, J, Liu, X, Yan, C, Wu, Y, Gong, X, Lei, X, S Yan, F, Radhakrishnan, A, Yan, N
JournalScience
Volume349
Issue6244
Pagination187-91
Date Published2015 Jul 10
ISSN1095-9203
KeywordsBacterial Proteins, Crystallography, X-Ray, Diglycerides, Humans, Hydroxycholesterols, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mycobacterium, Protein Multimerization, Protein Structure, Secondary, Sterol Regulatory Element Binding Proteins
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.

DOI10.1126/science.aab1091
Alternate JournalScience
PubMed ID26160948
PubMed Central IDPMC4704858
Grant ListP01 HL020948 / HL / NHLBI NIH HHS / United States
HL-20948 / HL / NHLBI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States