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UCP2

The UCP2 protein (mitochondrial uncoupling protein 2, also known as: BMIQ4, SLC25A8, UCPH ^{[1] [2] [3]}) is a widely expressed transmembrane protein found in mitochondria in different tissues such as white adipose and muscular tissues ^[4]. It allows an uncoupling of the electrochemical potential of the membrane in the respiratory chain of mitochondria by letting protons pass through the membrane, resulting in energy dissipation in form of heat. The protein is involved in preventing mitochondrial oxidative stress from accumulating ^[5]. It is found on chromosome 11 for Homo sapiens ^[6]. The UCP2 gene is found in primates (chimpanzee, rhesus monkey), in other mammals (dog, cow, mouse, rat), in fish, in insects (mosquito), in plants (A.thaliana, rice), in amphibians ^{[7] [8]} .

Structural properties

The protein consists of 309 amino acids, with domains located in the mitochondrial matrix, the inner mitochondrial membrane and in the intermembrane mitochondrial space. More precisely it can be described as a chain of and three amphipathic helices. The structure consists of three pseudo-repeats linking a transmembrane helix via a loop to an amphipathic helix, followed by another transmembrane alpha helix. ^[9]

Transmembrane helices are mainly composed of hydrophobic amino acids containing lots of alanine, valine, and leucine. ^[10] The determination and characterization of the structure of the membrane protein UCP2 was a difficulty that has been overcome thanks to a specific NMR method. This method combines two technics: 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 a Protein Data Bank) in order to determine local and secondary structures. Moreover, PRE restraints provide their spatial arrangement in the tertiary fold. ^[11]

Mechanism

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 the translocation with an emission of heat ^[12]. However, the mechanism of this proton translocation is unknown. UCP2 moreover functions as a chloride carrier. Some experiments were performed to find out more about the structure associated with this transport, in particular the positively charged transmembrane alpha helix (in the second pattern). Mutants were created lacking 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 has been observed that Cl- transport crucially decreases compared to the wild type. This positive alpha helix, therefore, is necessary to transport chloride-ions. ^[13] Moreover these experiments have shown that the positively charged domain allows precipitation of salts resulting in a dense packing in UCP2. This conformation amplifies the proton transport rate.

Regulation

Electron paramagnetic resonance studies showed conformational change in presence of long chain fatty acids. Fatty acids play a major role in the activation of the UCP2 protein. ^[14] Furthermore, it was observed that UCP2 is inhibited by GDP. Thus, 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 have shown, that the GDP binding site is close to the . ^[15]

Comparison to other mitochondrial uncoupling proteins

Other mitochondrial uncoupling proteins include UCP1 and UPC3, as well as UCP4 and UCP5. While UCP2 is widely expressed, UCP1 is expressed only in brown adipocytes, whereas UCP3 is expressed mainly in human skeletal muscle cells, existing in a long form and a short form. CP2 has a 59% homology to UCP1 and 73% to UCP3. UCP2 and UCP3 are likely to be ancestors of UCP1. ^{[16] [17]} While the structure of the protein is now well known, the mechanisms of uncoupling are more difficult to study. Understanding how the uncoupling proteins work is a key topic, as these proteins play a role in diseases such as cancer, obesity and vascular diseases. ^[18]

References

1. ↑ [[1]]
2. ↑ [[2]]
3. ↑ [[3]]
4. ↑ [[4]]
5. ↑ [5]Sophie Rousset, Marie-Clotilde Alves-Guerra, Julien Mozo, Bruno Miroux, Anne-Marie Cassard-Doulcier, Frédéric Bouillaud, Daniel Ricquier; The Biology of Mitochondrial Uncoupling Proteins. Diabetes 1 February 2004; 53 (suppl_1): S130–S135. https://doi.org/10.2337/diabetes.53.2007.S130
6. ↑ [[6]]
7. ↑ [[7]]
8. ↑ [[8]]
9. ↑ [9]Kream, E., Mitochondrial uncoupling protein 2
10. ↑ [10] UniProtKB - P70406 UCP2_MOUSE
11. ↑ [11]Ricquier, D., Bouillaud, F., (2000) The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP
12. ↑ [[12]]
13. ↑ [13]Hoang, T., Matovic, T., Parker, J., Smith, M.D., Jelokhani-Niaraki, M., Role of Positively Charged Residues of the Second Transmembrane Domain in the Ion Transport Activity and Conformation of Human Uncoupling Protein-2, Biochemistry 2015, 54, 14, 2303–2313,
14. ↑ [14]Kream, E., Mitochondrial uncoupling protein 2
15. ↑ [15] UniProtKB - P70406 UCP2_MOUSE
16. ↑ [16]Klaus-Ulrich Lentes, Naxin Tu, Hongmei Chen, Ulrike Winnikes, Irmtraud Reinert, Gaby Marmann & Karl Martin Pirke (1999) Genomic Organization and Mutational Analysis of the Human UCP2 Gene, a Prime Candidate Gene for Human Obesity, Journal of Receptors and Signal Transduction, 19:1-4, 229-244, DOI: 10.3109/10799899909036648
17. ↑ [17]Sophie Rousset, Marie-Clotilde Alves-Guerra, Julien Mozo, Bruno Miroux, Anne-Marie Cassard-Doulcier, Frédéric Bouillaud, Daniel Ricquier; The Biology of Mitochondrial Uncoupling Proteins. Diabetes 1 February 2004; 53 (suppl_1): S130–S135. https://doi.org/10.2337/diabetes.53.2007.S130
18. ↑ [18]Giorgia Pierelli, Rosita Stanzione, Maurizio Forte, Serena Migliarino, Marika Perelli, Massimo Volpe, Speranza Rubattu, "Uncoupling Protein 2: A Key Player and a Potential Therapeutic Target in Vascular Diseases", Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 7348372, 11 pages, 2017.https://doi.org/10.1155/2017/7348372