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SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain

Author

Listed:
  • Sebastian Hendrix

    (University of Amsterdam)

  • Vincent Dartigue

    (The University of Texas Southwestern Medical Center)

  • Hailee Hall

    (The University of Texas Southwestern Medical Center)

  • Shrankhla Bawaria

    (The University of Texas Southwestern Medical Center)

  • Jenina Kingma

    (University of Amsterdam)

  • Bilkish Bajaj

    (The University of Texas Southwestern Medical Center)

  • Noam Zelcer

    (University of Amsterdam)

  • Daniel L. Kober

    (The University of Texas Southwestern Medical Center)

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 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.

Suggested Citation

  • Sebastian Hendrix & Vincent Dartigue & Hailee Hall & Shrankhla Bawaria & Jenina Kingma & Bilkish Bajaj & Noam Zelcer & Daniel L. Kober, 2024. "SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50068-8
    DOI: 10.1038/s41467-024-50068-8
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    1. Sebastian Hendrix & Jenina Kingma & Roelof Ottenhoff & Masoud Valiloo & Monika Svecla & Lobke F. Zijlstra & Vinay Sachdev & Kristina Kovac & Johannes H. M. Levels & Aldo Jongejan & Jan F. Boer & Folke, 2023. "Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Anke Loregger & Matthijs Raaben & Joppe Nieuwenhuis & Josephine M. E. Tan & Lucas T. Jae & Lisa G. Hengel & Sebastian Hendrix & Marlene Berg & Saskia Scheij & Ji-Ying Song & Ivo J. Huijbers & Lona J. , 2020. "Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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    1. Sebastian Hendrix & Jenina Kingma & Roelof Ottenhoff & Masoud Valiloo & Monika Svecla & Lobke F. Zijlstra & Vinay Sachdev & Kristina Kovac & Johannes H. M. Levels & Aldo Jongejan & Jan F. Boer & Folke, 2023. "Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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