The extraction of membrane proteins from their native environment by detergents is central for their biophysical characterization. Recent studies have emphasized that detergents may perturb the structure
locally and modify the dynamics of membrane proteins.
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. 4
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 5
demonstrate how dodecylphosphocholine severely alters the structure as well as the function of UCP. The proposed strategy opens new vistas for probing the physiological relevance of three-dimensional structures of membrane proteins obtained in non-native environments.
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