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
Volume371
Issue6533
Date Published2021 03 05
ISSN1095-9203
KeywordsCryoelectron Microscopy, Humans, Hydroxycholesterols, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mutation, Protein Interaction Domains and Motifs
Abstract

<p>The sterol regulatory element-binding protein (SREBP) pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1 and -2, are membrane-embedded sterol sensors. The 25-hydroxycholesterol (25HC)-dependent association of Scap and Insig acts as the master switch for the SREBP pathway. Here, we present cryo-electron microscopy 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 angstrom. The sterol-sensing domain in Scap and all six TMs in Insig-2 were resolved. A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 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.</p>

DOI10.1126/science.abb2224
Alternate JournalScience
PubMed ID33446483