Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling.

Error message

Warning: A non-numeric value encountered in theme_biblio_tabular() (line 223 of /var/www/html/sites/all/modules/biblio/includes/
TitleMolecular determinants of inhibition of UCP1-mediated respiratory uncoupling.
Publication TypeJournal Article
Year of Publication2023
AuthorsGagelin A, Largeau C, Masscheleyn S, Piel MS, Calderón-Mora D, Bouillaud F, Hénin J, Miroux B
JournalNat Commun
Date Published2023 May 05
KeywordsAdipose Tissue, Brown, Fatty Acids, Ion Channels, Membrane Proteins, Mitochondrial Proteins, Purine Nucleotides, Saccharomyces cerevisiae, Uncoupling Protein 1

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.

Alternate JournalNat Commun
Citation Key2023|2164
PubMed ID37147287
PubMed Central IDPMC10162991