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Journal Article

Structural basis for lipid and copper regulation of the ABC transporter MsbA.


Hochberg,  Georg K. A.       
Max Planck Research Group Evolutionary Biochemistry, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;
Department of Chemistry, Philipps-Universität Marburg;
Center for Synthetic Microbiology, Philipps-Universität Marburg;

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Lyu, J., Liu, C., Zhang, T., Schrecke, S., Elam, N. P., Packianathan, C., et al. (2022). Structural basis for lipid and copper regulation of the ABC transporter MsbA. Nature communications, 13(1). doi:10.1038/s41467-022-34905-2.

Cite as: https://hdl.handle.net/21.11116/0000-000B-B26F-0
A critical step in lipopolysaccharide (LPS) biogenesis involves flipping lipooligosaccharide, an LPS precursor, from the cytoplasmic to the periplasmic leaflet of the inner membrane, an operation carried out by the ATP-binding cassette transporter MsbA. Although LPS binding to the inner cavity of MsbA is well established, the selectivity of MsbA-lipid interactions at other site(s) remains poorly understood. Here we use native mass spectrometry (MS) to characterize MsbA-lipid interactions and guide structural studies. We show the transporter co-purifies with copper(II) and metal binding modulates protein-lipid interactions. A 2.15A resolution structure of an N-terminal region of MsbA in complex with copper(II) is presented, revealing a structure reminiscent of the GHK peptide, a high-affinity copper(II) chelator. Our results demonstrate conformation-dependent lipid binding affinities, particularly for the LPS-precursor, 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)2-lipid A (KDL). We report a 3.6A-resolution structure of MsbA trapped in an open, outward-facing conformation with adenosine 5'-diphosphate and vanadate, revealing a distinct KDL binding site, wherein the lipid forms extensive interactions with the transporter. Additional studies provide evidence that the exterior KDL binding site is conserved and a positive allosteric modulator of ATPase activity, serving as a feedforward activation mechanism to couple transporter activity with LPS biosynthesis. © 2022. The Author(s).