Mitochondrial Uncoupling Protein 2
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Mitochondrial Uncoupling Protein 2 (UCP2) is an integral membrane transport protein that belongs to the family of mitochondrial solute carriers. UCP2 is made up of 309 amino acids, and it has a molecular weight of 33 kDa. Its biological function is to dissipate protons from a high to a low proton gradient from the inner membrane to the mitochondrial matrix. Translocation of these protons dissipates energy as heat, which has the potential to lower the production of reactive oxygen species (ROS) during ATP Synthesis. The potential health benefits of lowering levels of ROS will be discussed in further detail in the section 'Significance of UCP2'.
The secondary structure of UCP2 consists of three α-helical pseudo-repeats (or domains) that adopt a similar fold creating a channel-like structure. UCP2 is known to have a similar conformation to that of the bovine ADP/ATP carrier (ANT1).
Listed below are some of the similarities between UCP2 and ANT1. Overall, both proteins serve a similar function of molecule transportation in the mitochondria.
o Channel-like structure
o 3-psedo-repeats that adopt similar folds
o Kinks at prolines that are conserved in carrier-protein sequences
Each pseudo-repeat domain contains one amphipathic α-helix (APH), one odd-numbered and one even-numbered transmembrane α-helix (TMH), and one loop.
View Pseudo-repeatsIn UCP2, there are three APH, 2, 1, and 3, that loop to three TMH 1, 3, and 5, respectively. These APH have hydrophilic and hydrophobic residues that alternate at different residue lengths in every turn of the α-helix. At TMH 5, the APH rotates away from the channel protein at an angle of 45°. This rotation is different from the pattern seen on other similar proteins, which could be due to specificity of substrate binding. This confirmation opens the matrix side of the channel more than ANT1.
View APHEach of the three pseudo-repeat domains of UCP2 contain an odd-numbered and an even-numbered transmembrane α-helix (TMH). These TMH α-helices contain polar and non-polar regions that interact within mitochondrial membrane.
View TMHThe button below will allow for you to observe the APH (blue) and TMH (red) of the UCP2 protein. A loop to APH 2, 1, and 3 connects TMH 1, 3, and 5, respectively.
In the protein carrier family, there are known to be specific prolines that are conserved between all members of this family, including UCP2. In UCP2, these prolines are observed in the transmembrane helices (TMH) 1, 3, and 5, which have a kink at the proline residues 33, 136, and 234, respectively. Overall, structural similarity with small variations in the conserved fold suggests specificity of substrate binding and translocation per carrier-protein.
View Conserved Proline ResiduesThe mitochondrial membrane-bound protein has both polar and non-polar amino acids in each of the α-helices. The outer α-helices are mostly made up of non-polar amino acids, which interact with the non-polar, fatty acid tails of the phospholipids in the inner membrane of the mitochondria. The interior positioned α-helices are composed of mainly polar and charged amino acid residues, which allows for protons to be carried through the channel-like structure of UCP2.
View Hydrophobic & Hydrophilic RegionsUCP2 contains a GDP nucleotide-binding site in the C-terminal end (residues 276-298) (Ser, Phe, Leu, Arg, Leu, Gly, Ser, Trp, Asp, Val, Val, Met, Phe, Val, Thr, Tyr, Glu, Gln, Leu, Lys, Arg, Ala, Leu), which inhibits proton translocation activity. Overall, the amino acid residues present in the GDP- nucleotide-binding site have side-chains of acidic, basic, neutral, polar, and non-polar characteristics. A possible explanation for the variation in amino acids in this region could be because GDP is a purine nucleotide, composed of a nitrogen base (guanine) and two phosphate groups, which could result variety of complex interactions.
View GDP Nucleotide Binding SiteResearch has shown that UCP2 may be related to lowering the production of reactive oxygen species (ROS). The presence of ROS may be harmful to cells, as ROS have the ability to oxidize proteins and cause mutations in DNA. Mutations in DNA may lead to carcinogenesis and accelerated aging.
Additional research has found the expression of UCP2 in pancreatic β-cells leads to a decrease of insulin secretion, which may lead to diabetes. Inactivation of UCP2 by GDP-binding is able to restore the glucose-sensing pathway.
Other studies have shown UCP2 potential to be resistant to chemotherapy and able to perform metabolic reprogramming in cancer.
A more detailed analysis of UCP2 is necessary in order to be able to understand its role in human health.
Berardi, M., Shih, W., Harrison, S., & Chou, J. (2011). Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching. Nature, 476(7358), 109-113. Retrieved December 9, 2014, from Nature.
Weizmann Institute of Science. (2014). UCP2 Gene. Retrieved December 9, 2014, from http://www.genecards.org/cgi-bin/carddisp.pl?gene=UCP2&search=63e7309edc7cdb5a139ced0184bb6f86
Lee, F. (2009). Alpha Helix. Retrieved December 9, 2014, from http://www.web-books.com/MoBio/Free/Ch2C4.htm
Kream, E. (n.d.). MitochondrialUncouplingProtein2. Retrieved December 9, 2014, from https://collab.itc.virginia.edu/access/content/group/f85bed6c-45d2-4b18-b868-6a2353586804/Staging-3/Ch20_Mitochondrial_Uncoupling_Protein_2_Kream_E_index/Ch20_Mitochondrial_Uncoupling_Protein_2_Kream_E_index_MitochondrialUncouplingProtein2.html