AI Article Synopsis
- Brown adipose tissue utilizes uncoupling protein 1 (UCP1) to produce heat, making it a potential target for metabolic disorder treatments.
- Research reveals that purine nucleotides like GDP and GTP inhibit UCP1's respiration uncoupling by binding at a specific site, with key interactions involving certain amino acids.
- Mutations in specific residues (I187A and W281A) enhance UCP1 activity, highlighting how these changes can lead to increased uncoupling even in the presence of purine nucleotides.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10162991 | PMC |
| http://dx.doi.org/10.1038/s41467-023-38219-9 | DOI Listing |
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