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SUMMARY:Molecular determinants of inhibition of the Mitochondrial Uncoupli
 ng Protein 1­mediated respiratory uncoupling  - Dr Bruno Miroux
DTSTART:20241205T150000Z
DTEND:20241205T160000Z
UID:TALK225235@talks.cam.ac.uk
CONTACT:Lisa Arnold
DESCRIPTION:Brown adipose tissue expresses uncoupling protein 1 (UCP1)\, w
 hich dissipates energy as heat\, making it a target for treating metabolic
  disorders. Here\, we investigate how purine nucleotides inhibit respirati
 on 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 hydroph
 obic 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 result
 s provide a molecular understanding of the selective inhibition of UCP1 by
  purine nucleotides.2\n\n1. Moussa R.*\, Gellé R.\, Masscheleyn S.\, Pozz
 a A.\, Le Bon C.\, Moncoq K.\, Bonneté F. and Miroux B.*.Fine-tuning the 
 yeast GAL10 promoter and growth conditions for efficient recombinant membr
 ane protein production and purification (submitted).\n\n2. Gagelin\, A.\, 
 Largeau\, C.\, Masscheleyn\, S.\, Piel\, M.S.\, Calderón-Mora\, D.\, Boui
 llaud\, F.\, Hénin\, J.\, and Miroux\, B. (2023). Molecular determinants 
 of inhibition of UCP1-mediated respiratory uncoupling. Nat. Commun. 14\, 2
 594. https://doi.org/10.1038/s41467-023-38219-9.
LOCATION:MRC MBU\, Level 7 Lecture Theatre\, The Keith Peters Building\, C
 B2 0XY
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