title: Dangerous liaisons between detergents and membrane proteins. The case of mitochondrial uncoupling protein 2.
abstract: The extraction of membrane proteins from their native environment by detergents is central to their biophysical characterization. Recent studies have emphasized that detergents may perturb the structure locally and modify the dynamics of membrane proteins. However, it remains challenging to determine whether these perturbations are negligible or could be responsible for misfolded conformations, altering the protein's function. In this work, we propose an original strategy combining functional studies and molecular simulations to address the physiological relevance of membrane protein structures obtained in the presence of detergents. We apply our strategy to a structure of isoform 2 of an uncoupling protein (UCP2) binding an inhibitor recently obtained in dodecylphosphocholine detergent micelles. Although this structure shares common traits with the ADP/ATP carrier, a member of the same protein family, its functional and biological significance remains to be addressed. In the present investigation, we demonstrate how dodecylphosphocholine severely alters the structure as well as the function of UCPs. The proposed original strategy opens new vistas for probing the physiological relevance of three-dimensional structures of membrane proteins obtained in non-native environments.
authors.affiliation: CNRS UMR 7099, Institut de Biologie Physico Chimique (IBPC), 75005 Paris, France.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zoonens
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Comer
authors.forename: Sandrine
authors.initials: S
authors.lastname: Masscheleyn
authors.forename: Eva
authors.initials: E
authors.lastname: Pebay-Peyroula
authors.forename: Christophe
authors.initials: C
authors.lastname: Chipot
authors.forename: Bruno
authors.initials: B
authors.lastname: Miroux
authors.forename: François
authors.initials: F
authors.lastname: Dehez
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology*; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D011487:Protein Conformation; D000071246:Uncoupling Protein 2
chemical_list: D003902:Detergents; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000071246:Uncoupling Protein 2; D010767:Phosphorylcholine; C028810:dodecylphosphocholine