National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R00GM141261
United States
Citation
Journal: Nat Commun / Year: 2024 Title: SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain. Authors: Sebastian Hendrix / Vincent Dartigue / Hailee Hall / Shrankhla Bawaria / Jenina Kingma / Bilkish Bajaj / Noam Zelcer / Daniel L Kober / Abstract: Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also ...Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also required for a wide array of additional signaling pathways. A zymogen serine protease, S1P matures through autoproteolysis of two pro-domains, with one cleavage event in the endoplasmic reticulum (ER) and the other in the Golgi. We recently identified the SREBP regulating gene, (SPRING), which enhances S1P maturation and is necessary for SREBP signaling. Here, we report the cryo-EM structures of S1P and S1P-SPRING at sub-2.5 Å resolution. SPRING activates S1P by dislodging its inhibitory pro-domain and stabilizing intra-domain contacts. Functionally, SPRING licenses S1P to cleave its cognate substrate, SREBP2. Our findings reveal an activation mechanism for S1P and provide insights into how spatial control of S1P activity underpins cholesterol homeostasis.
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
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Electron microscopy
Microscope
TFS KRIOS
Specialist optics
Energy filter - Name: TFS Selectris / Energy filter - Slit width: 5 eV
Image recording
Film or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 6139 / Average exposure time: 3.5 sec. / Average electron dose: 55.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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