Molecular determinants of inhibition of the Mitochondrial Uncoupling Protein 1­mediated respiratory uncoupling

Add to your list(s) Download to your calendar using vCal

• Dr Bruno Miroux
• Thursday 05 December 2024, 15:00-16:00
• MRC MBU, Level 7 Lecture Theatre, The Keith Peters Building, CB2 0XY.

If you have a question about this talk, please contact Lisa Arnold.

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 assays1, both I187A and W281A mutants increase the fatty acid­induced 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.2

1. Moussa R., Gellé R., Masscheleyn S., Pozza A., Le Bon C., Moncoq K., Bonneté F. and Miroux B..Fine-tuning the yeast GAL10 promoter and growth conditions for efficient recombinant membrane protein production and purification (submitted).

2. Gagelin, A., Largeau, C., Masscheleyn, S., Piel, M.S., Calderón-Mora, D., Bouillaud, F., Hénin, J., and Miroux, B. (2023). Molecular determinants of inhibition of UCP1 -mediated respiratory uncoupling. Nat. Commun. 14, 2594. https://doi.org/10.1038/s41467-023-38219-9.

This talk is part of the MRC Mitochondrial Biology Unit Seminars series.

This talk is included in these lists:

• All Talks (aka the CURE list)
• CamBridgeSens
• Cambridge talks
• Life Science Interface Seminars
• MRC MBU, Level 7 Lecture Theatre, The Keith Peters Building, CB2 0XY
• MRC Mitochondrial Biology Unit Seminars
• Trust & Technology Initiative - interesting events

Note that ex-directory lists are not shown.