The ABC transporter MsbA in a dozen environments

Author:

Hoffmann Lea,Baier Anika,Jorde Lara,Kamel Michael,Schäfer Jan-Hannes,Schnelle Kilian,Scholz Alischa,Shvarev Dmitry,Wong Jaslyn E. M. M.,Parey KristianORCID,Januliene DovileORCID,Moeller ArneORCID

Abstract

AbstractHigh-resolution structure determination of membrane proteins typically requires isolation from the native lipid bilayer and reconstitution into artificial membrane mimics. For this purpose, numerous detergents, amphipols, polymers and membrane scaffold proteins are available. The choice of the specific membrane substitute can strongly affect the protein’s specific activity, stability and conformational spectrum, potentially leading to errors or misinterpretation during analysis. The bacterial ATP-binding cassette transporter MsbA is a prominent example of such environment-specific bias, resulting in apparent conformational and activity responses.Here, we present a systematic analysis of the conformational spectrum of MsbA, stabilized in a dozen environments, using cryo-EM. Our data show pronounced structural feedback of the ABC transporter to the respective membrane mimetics. Detergents generally favour a conformation with wide separation of the nucleotide-binding domains, while nanodiscs induce the narrow conformation. Notably, only three of the dozen tested environments allow MsbA to sample the functional conformational spectrum, enabling full movement of the nucleotide-binding domains between narrow and wide inward-facing conformations. We expect this study to serve as a blueprint for other membrane proteins, even where the structural reaction to the hydrophobic environment is not directly visible but still critical for the proteins’ function.

Publisher

Cold Spring Harbor Laboratory

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