Journal
CELL RESEARCH
Volume 26, Issue 11, Pages 1197-1211Publisher
SPRINGERNATURE
DOI: 10.1038/cr.2016.123
Keywords
lipid homeostasis; SREBP; SCAP
Categories
Funding
- Ministry of Science and Technology of China [2015CB9101012014, ZX09507003006]
- National Natural Science Foundation of China [31321062, 81590761]
- National Institute of Health [HL 077588]
- International Early Career Scientist grant from the Howard Hughes Medical Institute
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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 angstrom andryo-EM structure of the complex at 5.4 angstrom 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.
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