Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling

Antoine Gagelin, Corentin Largeau, Sandrine Masscheleyn, Mathilde S. Piel, Daniel Calderón-Mora, Frédéric Bouillaud, Jérôme Hénin () and Bruno Miroux ()
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Antoine Gagelin: Université Paris Cité, Laboratoire de Biochimie Théorique CNRS UPR9080
Corentin Largeau: Université Paris Cité, Laboratoire de Biochimie Théorique CNRS UPR9080
Sandrine Masscheleyn: Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild
Mathilde S. Piel: Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild
Daniel Calderón-Mora: Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild
Frédéric Bouillaud: Université Paris Cité, Institut Cochin, Inserm U1016, CNRS UMR8104
Jérôme Hénin: Université Paris Cité, Laboratoire de Biochimie Théorique CNRS UPR9080
Bruno Miroux: Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38219-9

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