The mitochondrial uncoupling protein UCP1: a gated pore.
The uncoupling protein UCP1 is a member of a superfamily of homologous proteins formed by the mitochondrial metabolite transporters. Although they act in vivo as carriers, under specific experimental conditions some of these transporters have been shown to behave as channels. This dual transport operation suggests that these carriers are likely to be formed by two differentiated functional and structural domains. The kinetic model termed "single binding center gated pore" is well suited to understand the behaviour of these carriers. It proposes that in the protein core there must exist a hydrophilic translocation pore whose access is controlled by gates. It is highly likely that the hydrophilic channel is formed by the transmembrane alpha-helices and that loops contribute to the formation of the gates. UCP1 is regulated physiologically by fatty acids and purine nucleotides. Nucleotides maintain the proton conductance inhibited while fatty acids act as cytosolic second messengers of noradrenaline to active UCP1. Based on photoaffinity labeling and mutagenesis data, we propose a structural model for the localization of the binding site. The nucleotide enters through a gate in the cytosolic side and binds deep inside the protein. The three matrix loops contribute to the formation of a hydrophobic binding pocket that would accommodate the purine moiety. Three arginine residues (in helices II, IV, and VI) would interact with the phosphate groups. His214 and Glu190 have been involved in the pH regulation of the nucleotide binding but because they are on the cytosolic side of the protein, we propose that their state of protonation will determine the access of the nucleotide to the binding center.
Arechaga
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I
MRC-Dunn Human Nutrition Unit, Cambridge, United Kingdom.
Ledesma
A
A
Rial
E
E
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D015640:Ion Channel Gating; D007473:Ion Channels; D017136:Ion Transport; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D009711:Nucleotides / Q000378:metabolism; D011522:Protons; D013438:Sulfhydryl Compounds / Q000378:metabolism; D000071256:Uncoupling Protein 1; D015003:Yeasts
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009711:Nucleotides; D011522:Protons; D013438:Sulfhydryl Compounds; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1