IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38219-9.html
   My bibliography  Save this article

Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling

Author

Listed:
  • Antoine Gagelin

    (Université Paris Cité, Laboratoire de Biochimie Théorique CNRS UPR9080
    Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild)

  • Corentin Largeau

    (Université Paris Cité, Laboratoire de Biochimie Théorique CNRS UPR9080
    Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild
    Université Paris Cité, Laboratoire de Biologie Physico-Chimique des Protéines Membranaires CNRS UMR7099)

  • Sandrine Masscheleyn

    (Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild
    Université Paris Cité, Laboratoire de Biologie Physico-Chimique des Protéines Membranaires CNRS UMR7099)

  • Mathilde S. Piel

    (Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild
    Université Paris Cité, Laboratoire de Biologie Physico-Chimique des Protéines Membranaires CNRS UMR7099)

  • Daniel Calderón-Mora

    (Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild
    Université Paris Cité, Laboratoire de Biologie Physico-Chimique des Protéines Membranaires CNRS UMR7099)

  • Frédéric Bouillaud

    (Université Paris Cité, Institut Cochin, Inserm U1016, CNRS UMR8104)

  • Jérôme Hénin

    (Université Paris Cité, Laboratoire de Biochimie Théorique CNRS UPR9080
    Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild)

  • Bruno Miroux

    (Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild
    Université Paris Cité, Laboratoire de Biologie Physico-Chimique des Protéines Membranaires CNRS UMR7099)

Abstract

Brown adipose tissue expresses uncoupling protein 1 (UCP1), which dissipates energy as heat, making it a target for treating metabolic disorders. Here, we investigate how purine nucleotides inhibit respiration uncoupling by UCP1. Our molecular simulations predict that GDP and GTP bind UCP1 in the common substrate binding site in an upright orientation, where the base moiety interacts with conserved residues R92 and E191. We identify a triplet of uncharged residues, F88/I187/W281, forming hydrophobic contacts with nucleotides. In yeast spheroplast respiration assays, both I187A and W281A mutants increase the fatty acid-induced uncoupling activity of UCP1 and partially suppress the inhibition of UCP1 activity by nucleotides. The F88A/I187A/W281A triple mutant is overactivated by fatty acids even at high concentrations of purine nucleotides. In simulations, E191 and W281 interact with purine but not pyrimidine bases. These results provide a molecular understanding of the selective inhibition of UCP1 by purine nucleotides.

Suggested Citation

  • Antoine Gagelin & Corentin Largeau & Sandrine Masscheleyn & Mathilde S. Piel & Daniel Calderón-Mora & Frédéric Bouillaud & Jérôme Hénin & Bruno Miroux, 2023. "Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38219-9
    DOI: 10.1038/s41467-023-38219-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38219-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-38219-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Ambre M. Bertholet & Edward T. Chouchani & Lawrence Kazak & Alessia Angelin & Andriy Fedorenko & Jonathan Z. Long & Sara Vidoni & Ryan Garrity & Joonseok Cho & Naohiro Terada & Douglas C. Wallace & Br, 2019. "H+ transport is an integral function of the mitochondrial ADP/ATP carrier," Nature, Nature, vol. 571(7766), pages 515-520, July.
    2. Vasiliki Mavridou & Martin S. King & Sotiria Tavoulari & Jonathan J. Ruprecht & Shane M. Palmer & Edmund R. S. Kunji, 2022. "Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Marcelo J. Berardi & William M. Shih & Stephen C. Harrison & James J. Chou, 2011. "Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching," Nature, Nature, vol. 476(7358), pages 109-113, August.
    4. Eva Pebay-Peyroula & Cécile Dahout-Gonzalez & Richard Kahn & Véronique Trézéguet & Guy J.-M. Lauquin & Gérard Brandolin, 2003. "Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside," Nature, Nature, vol. 426(6962), pages 39-44, November.
    5. Emmanouela Tsagkaraki & Sarah M. Nicoloro & Tiffany DeSouza & Javier Solivan-Rivera & Anand Desai & Lawrence M. Lifshitz & Yuefei Shen & Mark Kelly & Adilson Guilherme & Felipe Henriques & Nadia Amran, 2021. "CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    6. Ambre M. Bertholet & Andrew M. Natale & Paola Bisignano & Junji Suzuki & Andriy Fedorenko & James Hamilton & Tatiana Brustovetsky & Lawrence Kazak & Ryan Garrity & Edward T. Chouchani & Nickolay Brust, 2022. "Mitochondrial uncouplers induce proton leak by activating AAC and UCP1," Nature, Nature, vol. 606(7912), pages 180-187, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Pavel Dolezal & Michael J Dagley & Maya Kono & Peter Wolynec & Vladimir A Likić & Jung Hock Foo & Miroslava Sedinová & Jan Tachezy & Anna Bachmann & Iris Bruchhaus & Trevor Lithgow, 2010. "The Essentials of Protein Import in the Degenerate Mitochondrion of Entamoeba histolytica," PLOS Pathogens, Public Library of Science, vol. 6(3), pages 1-13, March.
    2. Bi-Qing Li & Le-Le Hu & Lei Chen & Kai-Yan Feng & Yu-Dong Cai & Kuo-Chen Chou, 2012. "Prediction of Protein Domain with mRMR Feature Selection and Analysis," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-14, June.
    3. Erminia Donnarumma & Michael Kohlhaas & Elodie Vimont & Etienne Kornobis & Thibault Chaze & Quentin Giai Gianetto & Mariette Matondo & Maryse Moya-Nilges & Christoph Maack & Timothy Wai, 2022. "Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    4. Xiaoting Sun & Wenhai Sui & Zepeng Mu & Sisi Xie & Jinxiu Deng & Sen Li & Takahiro Seki & Jieyu Wu & Xu Jing & Xingkang He & Yangang Wang & Xiaokun Li & Yunlong Yang & Ping Huang & Minghua Ge & Yihai , 2023. "Mirabegron displays anticancer effects by globally browning adipose tissues," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Xiaojian Shi & Bryn Reinstadler & Hardik Shah & Tsz-Leung To & Katie Byrne & Luanna Summer & Sarah E. Calvo & Olga Goldberger & John G. Doench & Vamsi K. Mootha & Hongying Shen, 2022. "Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Chen, Shuxian & Dai, Xiaohu & Yang, Donghai & Dai, Lingling & Hua, Yu, 2023. "Enhancing PHA production through metal-organic frameworks: Mechanisms involving superproton transport and bacterial metabolic pathways," Applied Energy, Elsevier, vol. 348(C).
    7. Robert Dobosz & Jan Mućko & Ryszard Gawinecki, 2020. "Using Chou’s 5-Step Rule to Evaluate the Stability of Tautomers: Susceptibility of 2-[(Phenylimino)-methyl]-cyclohexane-1,3-diones to Tautomerization Based on the Calculated Gibbs Free Energies," Energies, MDPI, vol. 13(1), pages 1-14, January.
    8. Vasiliki Mavridou & Martin S. King & Sotiria Tavoulari & Jonathan J. Ruprecht & Shane M. Palmer & Edmund R. S. Kunji, 2022. "Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    9. M. Kyle Cromer & Valentin V. Barsan & Erich Jaeger & Mengchi Wang & Jessica P. Hampton & Feng Chen & Drew Kennedy & Jenny Xiao & Irina Khrebtukova & Ana Granat & Tiffany Truong & Matthew H. Porteus, 2022. "Ultra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Jacqueline A. Turner & Malia A. Fredrickson & Marc D’Antonio & Elizabeth Katsnelson & Morgan MacBeth & Robert Gulick & Tugs-Saikhan Chimed & Martin McCarter & Angelo D’Alessandro & William A. Robinson, 2023. "Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38219-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.