Structural basis for sterol sensing by Scap and Insig.

TitleStructural basis for sterol sensing by Scap and Insig.
Publication TypeJournal Article
Year of Publication2021
AuthorsYan, R, Cao, P, Song, W, Li, Y, Wang, T, Qian, H, Yan, C, Yan, N
JournalCell Rep
Volume35
Issue13
Pagination109299
Date Published2021 Jun 29
ISSN2211-1247
Abstract

The sterol regulatory element-binding protein (SREBP) pathway monitors the cellular cholesterol level through sterol-regulated association between the SREBP cleavage-activating protein (Scap) and the insulin-induced gene (Insig). Despite structural determination of the Scap and Insig-2 complex bound to 25-hydroxycholesterol, the luminal domains of Scap remain unresolved. In this study, combining cryogenic electron microscopy (cryo-EM) analysis and artificial intelligence-facilitated structural prediction, we report the structure of the human Scap/Insig-2 complex purified in digitonin. The luminal domain loop 1 and a co-folded segment in loop 7 of Scap resemble those of the luminal/extracellular domain in NPC1 and related proteins, providing clues to the cholesterol-regulated interaction of loop 1 and loop 7. An additional luminal interface is observed between Scap and Insig. We also show that Scap(D428A), which inhibits SREBP activation even under sterol depletion, exhibits an identical conformation with the wild-type protein when complexed with Insig-2, and its constitutive suppression of the SREBP pathway may also involve a later step in protein trafficking.

DOI10.1016/j.celrep.2021.109299
Alternate JournalCell Rep
PubMed ID34192549