A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols.

TitleA structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols.
Publication TypeJournal Article
Year of Publication2021
AuthorsYan, R, Cao, P, Song, W, Qian, H, Du, X, Coates, HW, Zhao, X, Li, Y, Gao, S, Gong, X, Liu, X, Sui, J, Lei, J, Yang, H, Brown, AJ, Zhou, Q, Yan, C, Yan, N
JournalScience
Date Published2021 Jan 14
ISSN1095-9203
Abstract

The SREBP pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1/2, are membrane-embedded sterol sensors. 25-hydroxycholesterol (25HC)-dependent association of Scap and Insigs acts as the master switch for the SREBP pathway. Here, we present cryo-EM analysis of the human Scap and Insig-2 complex in the presence of 25HC, with the transmembrane (TM) domains determined at an average resolution of 3.7 Å. The sterol sensing domain (SSD) in Scap and all six TMs in Insig-2 were resolved. A 25HC molecule is sandwiched between the S4-S6 segments in Scap and TMs 3/4 in Insig-2 in the luminal leaflet of the membrane. Unwinding of the middle of the Scap-S4 segment is crucial for 25HC binding and Insig association.

DOI10.1126/science.abb2224
Alternate JournalScience
PubMed ID33446483