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The UCP2 protein is a transmembrane protein found in mitochondrias in different tissues such as white adipose and muscular tissues. This protein allows an uncoupling of the electrochemical potential of membrane in the respiratory chain of mitochondria resulting in a heat creation. This protein is a carrier of protons and chlorides.

A transmembrane protein

UCP2 is 309 amino acids long with domains located in the mitochondrial matrix, in the inner mitochondrial membrane and in the intermembrane mitochondrial space. More precisely it can be described as a chain of six transmembrane helices and three amphipathic helices. The structure consists of three pseudo-repeats in which a transmembrane helix is linked by a loop to an amphipathic helix, followed by another transmembrane alpha helix. In addition, transmembrane helices are mainly composed of Hydrophobic amino acids with a lot of alanine, valine and leucine. Membrane-protein structure determination and characterisation of UCP2 is a difficulty which is overcomed thanks to a specific NMR method. This method combines two technics : first, the use of NMR residual dipolar couplings (RDCs) which give orientation restraints and Paramagnetic Relaxation Enhancement (PRE) which determines distance restraints. Experimental RDCs of UCP2 were compared to assemblies of known molecular fragments (from the Protein Data Bank) aiming the determination of the local and secondary structures. Moreover, PRE restraints provide their spatial arrangement in the tertiary fold.

An ion carrier protein

It is known that the electrochemical potential of the inner mitochondrial membrane is due to a proton gradient. UCP2 allows to translocate protons to the mitochondrial matrix (following the exergonic direction) and to couple that with heat emission. However, the mechanism of this proton translocation is unknown. UCP2 is also a chloride carrier. Some experiments were carried out about the structure related to this transport particularly about the positively charged transmembrane alpha helix (in the second pattern). Mutants were created without positive charged amino acids (arginine and lysine muted in glutamine) : R76Q, R88Q, R96Q, and K104Q. After purification and insertion of those mutants in liposomes it is observed that Cl- transport crucially decreases compared with the wild type. So this positive alpha helix is necessary to chloride transport. Those experiments also shown that this positively charged domain allows precipitation of salts resulting in a dense packing in UCP2. This conformation significantly increases the proton transport rate.

A regulated protein

Some electron paramagnetic resonance studies show a changement of conformation in presence of fatty acids with long chains. Fatty acids are necessary to the setting up of the active form of the UCP2. It is also observed that the UCP2 is inhibited by GDP. In that a low cellular energy level will favor the production of ATP by the ATP synthase at the end of the respiratory chain instead of uncoupling. Some experiments with mutants show that the GDP binding site is closer to the helices 1 and 4

If the structure of the protein is today well known, the mechanisms of the uncoupling are harder to study. The understanding of the uncoupling proteins’ running is a key issue because those proteins are implicated in some diseases such as cancers or obesity.

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