Sandbox Reserved 1662

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This Sandbox is Reserved from 26/11/2020, through 26/11/2021 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1643 through Sandbox Reserved 1664.
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UCP2

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The uncoupling protein 2 (UCP2) protein is a transmembrane protein found in the mitochondria of various tissues such as white adipose tissue and muscle tissue. This protein allows uncoupling of the membrane electrochemical potential in the mitochondrial respiratory chain, resulting in heat generation. This protein is a carrier of protons and chlorides.The UCP2 protein is found in Homo sapiens and it is known under other names: BMIQ4, SLC25A8, UCPH. The gene coding for this protein is found on the chromosome 11 and has 5 transcripts for Homo sapiens.

A transmembrane protein

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. [1]

Transmembrane helices are mainly composed of hydrophobic amino acids containing lots of alanine, valine, and leucine. [2] 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. [3]


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 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 (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. [4] 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.


A regulated protein

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. [5] 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 [6]

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 or obesity.



References

  1. ↑ [1]Kream, E., Mitochondrial uncoupling protein 2
  2. ↑ [2] UniProtKB - P70406 UCP2_MOUSE
  3. ↑ [3]Ricquier, D., Bouillaud, F., (2000) The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP
  4. ↑ [4]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,
  5. ↑ [5]Kream, E., Mitochondrial uncoupling protein 2
  6. ↑ [6] UniProtKB - P70406 UCP2_MOUSE
Further information about this protein:

http://may2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000175567;r=11:73974667-73983307 http://may2017.archive.ensembl.org/Mus_musculus/Gene/Summary?db=core;g=ENSMUSG00000033685 https://www.proteinatlas.org/ENSG00000175567-UCP2/tissue https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7351 https://www.genecards.org/cgi-bin/carddisp.pl?gene=UCP2 https://datamed.org/display-item.php?repository=0002&id=5952dfd35152c64c3b10b93c&query=UCP2 https://humancyc.org/gene?orgid=HUMAN&id=HS10953

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