Fatty acids change the conformation of uncoupling protein 1 (UCP1).

TitleFatty acids change the conformation of uncoupling protein 1 (UCP1).
Publication TypeJournal Article
Year of Publication2012
AuthorsDivakaruni, AS, Humphrey, DM, Brand, MD
JournalJ Biol Chem
Volume287
Issue44
Pagination36845-53
Date Published2012 Oct 26
ISSN1083-351X
KeywordsAdipose Tissue, Brown, Animals, Binding, Competitive, Female, Fluorescent Dyes, Guanosine Diphosphate, Ion Channels, Kinetics, Membrane Potential, Mitochondrial, Mice, Mice, Knockout, Mitochondria, Mitochondrial Proteins, ortho-Aminobenzoates, Palmitates, Protein Binding, Protein Conformation, Proteolysis, Rats, Rats, Wistar, Thymus Gland, Trypsin, Uncoupling Protein 1
Abstract

UCP1 catalyzes proton leak across the mitochondrial inner membrane to disengage substrate oxidation from ATP production. It is well established that UCP1 is activated by fatty acids and inhibited by purine nucleotides, but precisely how this regulation occurs remains unsettled. Although fatty acids can competitively overcome nucleotide inhibition in functional assays, fatty acids have little effect on purine nucleotide binding. Here, we present the first demonstration that fatty acids induce a conformational change in UCP1. Palmitate dramatically changed the binding kinetics of 2'/3'-O-(N-methylanthraniloyl)-GDP, a fluorescently labeled nucleotide analog, for UCP1. Furthermore, palmitate accelerated the rate of enzymatic proteolysis of UCP1. The altered kinetics of both processes indicate that fatty acids change the conformation of UCP1, reconciling the apparent discrepancy between existing functional and ligand binding data. Our results provide a framework for how fatty acids and nucleotides compete to regulate the activity of UCP1.

DOI10.1074/jbc.M112.381780
Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M112.381780
PubMed ID22952235
PubMed Central IDPMC3481287
Grant ListP01 AG025901 / AG / NIA NIH HHS / United States
PL1 AG032118 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom