Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization

Xin Gong, Hongwu Qian, Wei Shao, Jingxian Li, Jianping Wu, Jun Jie Liu, Wenqi Li, Hong Wei Wang, Peter Espenshade, Nieng Yan

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Sterol regulatory element-binding protein (SREBP) transcription factors are master regulators of cellular lipid homeostasis in mammals and oxygen-responsive regulators of hypoxic adaptation in fungi. SREBP C-terminus binds to the WD40 domain of SREBP cleavage-activating protein (SCAP), which confers sterol regulation by controlling the ER-to-Golgi transport of the SREBP-SCAP complex and access to the activating proteases in the Golgi. Here, we biochemically and structurally show that the carboxyl terminal domains (CTD) of Sre1 and Scp1, the fission yeast SREBP and SCAP, form a functional 4:4 oligomer and Sre1-CTD forms a dimer of dimers. The crystal structure of Sre1-CTD at 3.5 Å and cryo-EM structure of the complex at 5.4 Å together with in vitro biochemical evidence elucidate three distinct regions in Sre1-CTD required for Scp1 binding, Sre1-CTD dimerization and tetrameric formation. Finally, these structurally identified domains are validated in a cellular context, demonstrating that the proper 4:4 oligomeric complex formation is required for Sre1 activation.

Original languageEnglish (US)
Pages (from-to)1197-1211
Number of pages15
JournalCell Research
Volume26
Issue number11
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

  • SCAP
  • SREBP
  • lipid homeostasis

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  • Cite this

    Gong, X., Qian, H., Shao, W., Li, J., Wu, J., Liu, J. J., Li, W., Wang, H. W., Espenshade, P., & Yan, N. (2016). Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization. Cell Research, 26(11), 1197-1211. https://doi.org/10.1038/cr.2016.123