Dangerous Liaisons between Detergents and Membrane Proteins. The Case of Mitochondrial Uncoupling Protein 2
- 26 September 2013
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 135 (40), 15174-15182
- https://doi.org/10.1021/ja407424v
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.Keywords
This publication has 67 references indexed in Scilit:
- Mapping the Nucleotide Binding Site of Uncoupling Protein 1 Using Atomic Force MicroscopyJournal of the American Chemical Society, 2013
- Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat MitochondriaCell, 2012
- Dramatic Destabilization of Transmembrane Helix Interactions by Features of Natural Membrane EnvironmentsJournal of the American Chemical Society, 2011
- Influence of solubilizing environments on membrane protein structuresTrends in Biochemical Sciences, 2011
- Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid TypesThe Journal of Physical Chemistry B, 2010
- High-Chloride Concentrations Abolish the Binding of Adenine Nucleotides in the Mitochondrial ADP/ATP Carrier FamilyBiophysical Journal, 2009
- CHARMM-GUI Membrane Builder for Mixed Bilayers and Its Application to Yeast MembranesBiophysical Journal, 2009
- Scalable molecular dynamics with NAMDJournal of Computational Chemistry, 2005
- All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of ProteinsThe Journal of Physical Chemistry B, 1998
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996