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<Structure load='2lck' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | <Structure load='2lck' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | ||
The UCP2 protein (mitochondrial uncoupling protein 2, also known as: BMIQ4, SLC25A8, UCPH) is a widely expressed transmembrane protein found in mitochondria in different tissues such as white adipose and muscular tissues. 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 | The UCP2 protein (mitochondrial uncoupling protein 2, also known as: BMIQ4, SLC25A8, UCPH <ref>[[http://may2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000175567;r=11:73974667-73983307]] </ref> <ref>[[https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7351]] </ref> <ref>[[https://www.genecards.org/cgi-bin/carddisp.pl?gene=UCP2]] </ref>) is a widely expressed transmembrane protein found in mitochondria in different tissues such as white adipose and muscular tissues <ref>[[https://www.proteinatlas.org/ENSG00000175567-UCP2/tissue]]</ref>. 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 <ref> | ||
[https://doi.org/10.2337/diabetes.53.2007.S130]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 </ref> | [https://doi.org/10.2337/diabetes.53.2007.S130]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 </ref>. It is found on chromosome 11 for Homo sapiens <ref>[[https://humancyc.org/gene?orgid=HUMAN&id=HS10953]] </ref>. 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 <ref>[[https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7351]] </ref> <ref>[[http://may2017.archive.ensembl.org/Mus_musculus/Gene/Summary?db=core;g=ENSMUSG00000033685;r=7:100493337-100502020]]</ref> . | ||
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== Mechanism == | == 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. 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 <scene name='86/868195/Tm2/1'>TM2</scene> (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. <ref>[https://doi.org/10.1021/acs.biochem.5b00177]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, </ref> | 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 <ref>[[https://www.genecards.org/cgi-bin/carddisp.pl?gene=UCP2]] </ref>. 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 <scene name='86/868195/Tm2/1'>TM2</scene> (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. <ref>[https://doi.org/10.1021/acs.biochem.5b00177]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, </ref> | ||
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. | 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. | ||
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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. <ref>[https://collab.its.virginia.edu/access/content/group/f85bed6c-45d2-4b18-b868-6a2353586804/2/Ch20_Kream_E_Uncoupling_Protein_2_(Mitochondrial)-_-/Ch20_Kream_E_Uncoupling_Protein_2_(Mitochondrial)_MitochondrialUncouplingProtein2.html]Kream, E., Mitochondrial uncoupling protein 2 </ref> | 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. <ref>[https://collab.its.virginia.edu/access/content/group/f85bed6c-45d2-4b18-b868-6a2353586804/2/Ch20_Kream_E_Uncoupling_Protein_2_(Mitochondrial)-_-/Ch20_Kream_E_Uncoupling_Protein_2_(Mitochondrial)_MitochondrialUncouplingProtein2.html]Kream, E., Mitochondrial uncoupling protein 2 </ref> | ||
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 <scene name='86/868195/Helices_1_and_4/1'>helices 1 and 4</scene> <ref>[https://www.uniprot.org/uniprot/P70406] UniProtKB - P70406 UCP2_MOUSE </ref> | 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 <scene name='86/868195/Helices_1_and_4/1'>helices 1 and 4</scene>. <ref>[https://www.uniprot.org/uniprot/P70406] UniProtKB - P70406 UCP2_MOUSE </ref> | ||
== Comparison to other mitochondrial uncoupling proteins == | == 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. <ref> [https://doi.org/10.3109/10799899909036648]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 <ref> | 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. <ref> [https://doi.org/10.3109/10799899909036648]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 </ref> | ||
<ref> | <ref> | ||
[https://diabetesjournals.org/diabetes/article/53/suppl_1/S130/11581/The-Biology-of-Mitochondrial-Uncoupling-Proteins]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 </ref> | [https://diabetesjournals.org/diabetes/article/53/suppl_1/S130/11581/The-Biology-of-Mitochondrial-Uncoupling-Proteins]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 </ref> | ||
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. | 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. | ||
<ref> [https://doi.org/10.1155/2017/7348372]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 <ref> | <ref> [https://doi.org/10.1155/2017/7348372]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 </ref> | ||
== References == | == References == | ||
<references/> | <references/> | ||
