Retrospective on Cholesterol Homeostasis: The Central Role of Scap

Research output: Contribution to journalReview article

68 Scopus citations

Abstract

Scap is a polytopic membrane protein that functions as a molecular machine to control the cholesterol content of membranes in mammalian cells. In the 21 years since our laboratory discovered Scap, we have learned how it binds sterol regulatory element-binding proteins (SREBPs) and transports them from the endoplasmic reticulum (ER) to the Golgi for proteolytic processing. Proteolysis releases the SREBP transcription factor domains, which enter the nucleus to promote cholesterol synthesis and uptake. When cholesterol in ER membranes exceeds a threshold, the sterol binds to Scap, triggering several conformational changes that prevent the Scap-SREBP complex from leaving the ER. As a result, SREBPs are no longer processed, cholesterol synthesis and uptake are repressed, and cholesterol homeostasis is restored. This review focuses on the four domains of Scap that undergo concerted conformational changes in response to cholesterol binding. The data provide a molecular mechanism for the control of lipids in cell membranes.

Original languageEnglish (US)
Pages (from-to)783-807
Number of pages25
JournalAnnual Review of Biochemistry
Volume87
DOIs
StatePublished - Jun 20 2018

Keywords

  • cholesterol
  • conformational changes
  • COPII vesicles
  • ER-to-Golgi transport
  • Insig
  • membrane proteins
  • proteolytic processing
  • Scap
  • SREBPs
  • transcriptional regulation

ASJC Scopus subject areas

  • Biochemistry

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