Volume 26, No 11, Nov 2016
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 26 Issue 11, November 2016: 1197-1211 | Open Access
ORIGINAL ARTICLES
Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization
Xin Gong1,2,3,*, Hongwu Qian1,2,3,*, Wei Shao4,*, Jingxian Li1,2, Jianping Wu1,2,3, Jun-Jie Liu2,3, Wenqi Li1,2, Hong-Wei Wang2,3, Peter Espenshade4 and Nieng Yan1,2,3
1State Key Laboratory of Membrane Biology, Beijing 100084, China
2Beijing Advanced Innovation Center for Structural Biology, Beijing 100084, China
3Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China
4Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Correspondence: Nieng Yan, E-mail: nyan@tsinghua.edu.cn; Peter Espenshade, E-mail: peter.espenshade@jhmi.edu
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.
10.1038/cr.2016.123
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