A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols.
basic_science · Level V
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- Record sourced from PubMed, PMID 33446483.
- Also identified by DOI 10.1126/science.abb2224.
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Abstract
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.
Medical subject headings
- Hydroxycholesterols
- Intracellular Signaling Peptides and Proteins
- Membrane Proteins
- Protein Interaction Domains and Motifs