Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPS) and SREBP cleavage-activating protein

Juro Sakai, Axel Nohturfft, Dong Cheng, Y. K. Ho, Michael S. Brown, Joseph L. Goldstein

Research output: Contribution to journalArticle

182 Scopus citations

Abstract

SREBP cleavage-activating protein (SCAP) stimulates the proteolytic cleavage of membrane-bound SREBPs, thereby initiating the release of NH2- terminal fragments from cell membranes. The liberated fragments enter the nucleus and stimulate transcription of genes involved in synthesis and uptake of cholesterol and fatty acids. Sterols repress cleavage of SREBPs, apparently by interacting with the membrane attachment domain of SCAP. In the present studies we show that SCAP, like the SREBPs, is located in membranes of the endoplasmic reticulum and nuclear envelope. The COOH-terminal domain of SCAP, like that of the SREBPs, is located on the cytosolic face of the membranes. Co-immunoprecipitation experiments show that SCAP and SREBP-2 form a complex that can be precipitated with antibodies to either component. Complex formation occurs when cells express only the COOH-terminal domain of either SREBP-2 or SCAP, indicating that the complex forms between the two COOH-terminal domains. Truncation of SREBP-2 at its COOH terminus prevents the formation of complexes with SCAP and simultaneously reduces proteolytic cleavage. We conclude that proteolytic cleavage of SREBPs requires the formation of a complex with the COOH-terminal domain of SCAP and that SCALP is therefore a required element in the regulation of sterol and fatty acid metabolism in animal cells.

Original languageEnglish (US)
Pages (from-to)20213-20221
Number of pages9
JournalJournal of Biological Chemistry
Volume272
Issue number32
DOIs
StatePublished - Aug 8 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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