title: Toward understanding the mechanism of ion transport activity of neuronal uncoupling proteins UCP2, UCP4, and UCP5.
abstract: Neuronal uncoupling proteins (UCP2, UCP4, and UCP5) have crucial roles in the function and protection of the central nervous system (CNS). Extensive biochemical studies of UCP2 have provided ample evidence of its participation in proton and anion transport. To date, functional studies of UCP4 and UCP5 are scarce. In this study, we show for the first time that, despite a low level of amino acid sequence identity with the previously characterized UCPs (UCP1-UCP3), UCP4 and UCP5 share their functional properties. Recombinantly expressed in Escherichia coli, UCP2, UCP4, and UCP5 were isolated and reconstituted into liposome systems, where their conformations and ion (proton and chloride) transport properties were examined. All three neuronal UCPs are able to transport protons across lipid membranes with characteristics similar to those of the archetypal protein UCP1, which is activated by fatty acids and inhibited by purine nucleotides. Neuronal UCPs also exhibit transmembrane chloride transport activity. Circular dichroism spectroscopy shows that these three transporters exist in different conformations. In addition, their structures and functions are differentially modulated by the mitochondrial lipid cardiolipin. In total, this study supports the existence of general conformational and ion transport features in neuronal UCPs. On the other hand, it also emphasizes the subtle structural and functional differences between UCPs that could distinguish their physiological roles. Differentiation between structure-function relationships of neuronal UCPs is essential for understanding their physiological functions in the CNS.
authors.affiliation: Department of Chemistry, Wilfrid Laurier University, Waterloo, ON, Canada.
authors.forename: Tuan
authors.initials: T
authors.lastname: Hoang
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Smith
authors.forename: Masoud
authors.initials: M
authors.lastname: Jelokhani-Niaraki
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D002308:Cardiolipins / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D002942:Circular Dichroism; D004926:Escherichia coli / Q000235:genetics; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D008081:Liposomes / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071245:Mitochondrial Uncoupling Proteins; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011487:Protein Conformation; D011522:Protons; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D002308:Cardiolipins; D002712:Chlorides; D007473:Ion Channels; D008081:Liposomes; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D000071245:Mitochondrial Uncoupling Proteins; D009419:Nerve Tissue Proteins; D011522:Protons; D011994:Recombinant Proteins; C116584:SLC25A14 protein, human; C117577:SLC25A27 protein, human; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate