The Mitochondrial Uncoupling Protein UCP1: A Gated Pore

Abstract

SummaryThe 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 speci c 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 ®-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 photoaf nity 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 hydrophobi c 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.

UCP3 Expression in Liver Modulates Gene Expression and Oxidative Metabolism in Response to Fatty Acids, and Sensitizes Mitochondria to Permeability Transition

“…Moreover, the mechanisms by which UCP3 favors this phenomenon should also be further investigated, and either indirect effects (via modulation of the mitochondrial membrane potential) or direct effects could be hypothesised. In this last sense, members of the mitochondrial transporter family such as the adenine nucleotide translocase or the phosphate carrier, and even UCPs, have been shown to be capable of acquiring a pore conformation under certain conditions thus favoring permeability transition [16,39,40], and it cannot be excluded that UCP3, as a member of this protein family, was also directly involved. Finally, the observation that the presence of UCP3 induces changes in nuclear gene expression lead to the consideration that some of the effects observed in UCP3-expressing mitochondria could be indirect.…”

Body size, energy metabolism and lifespan

“…The membrane potential of mitochondria can, however, be influenced by activated channels (Arechaga et al, 2001) that permit protons in the intermembrane space to move across the membrane without passing through complex V and generating ATP. Some of these protein channels are called uncoupling proteins (UCPs) because they uncouple the association between protein movement and ATP production (Klaus et al, 1991;Jezek, 2002) but other compounds also dissipate the proton gradient by translocating other charges across the membrane -such as the adenine nucleotide translocase (ANT).…”

Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities

“…ATP synthase (F 0 · F 1 -ATPase), also called complex V, consists of a joined membrane-bound F 0 -ATPase and apparently attached rotatory F 1 -ATPase. The complex is capable of ''coupling'' proton flow to conversion of ADP to ATP in an intricate manner that still remains incompletely understood (16).…”