Structure of the WD40 domain of SCAP from fission yeast reveals the molecular basis for SREBP recognition

Xin Gong, Jingxian Li, Wei Shao, Jianping Wu, Hongwu Qian, Ruobing Ren, Peter Espenshade, Nieng Yan

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP) are central players in the SREBP pathway, which control the cellular lipid homeostasis. SCAP binds to SREBP through their carboxyl (C) domains and escorts SREBP from the endoplasmic reticulum to the Golgi upon sterol depletion. A conserved pathway, with the homologues of SREBP and SCAP being Sre1 and Scp1, was identified in fission yeast Schizosaccharomyces pombe. Here we report the in vitro reconstitution of the complex between the C domains of Sre1 and Scp1 as well as the crystal structure of the WD40 domain of Scp1 at 2.1 Å resolution. The structure reveals an eight-bladed β-propeller that exhibits several distinctive features from a canonical WD40 repeat domain. Structural and biochemical characterization led to the identification of two Scp1 elements that are involved in Sre1 recognition, an Arg/Lys-enriched surface patch on the top face of the WD40 propeller and a 30-residue C-terminal tail. The structural and biochemical findings were corroborated by in vivo examinations. These studies serve as a framework for the mechanistic understanding and further functional characterization of the SREBP and SCAP proteins in fission yeast and higher organisms.

Original languageEnglish (US)
Pages (from-to)401-411
Number of pages11
JournalCell Research
Volume25
Issue number4
DOIs
StatePublished - Apr 8 2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

  • Lipid homeostasis
  • SCAP
  • SREBP
  • Structure

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