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Structure and lipid dynamics in the maintenance of lipid asymmetry inner membrane complex of A. baumannii

Structure and lipid dynamics in the maintenance of lipid asymmetry inner membrane complex of A. baumannii
Structure and lipid dynamics in the maintenance of lipid asymmetry inner membrane complex of A. baumannii
Multi-resistant bacteria are a major threat in modern medicine. The gram-negative coccobacillus Acinetobacter baumannii currently leads the WHO list of pathogens in critical need for new therapeutic development. The maintenance of lipid asymmetry (MLA) protein complex is one of the core machineries that transport lipids from/to the outer membrane in gram-negative bacteria. It also contributes to broad-range antibiotic resistance in several pathogens, most prominently in A. baumannii. Nonetheless, the molecular details of its role in lipid transport has remained largely elusive. Here, we report the cryo-EM maps of the core MLA complex, MlaBDEF, from the pathogen A. baumannii, in the apo-, ATP- and ADP-bound states, revealing multiple lipid binding sites in the cytosolic and periplasmic side of the complex. Molecular dynamics simulations suggest their potential trajectory across the membrane. Collectively with the recently-reported structures of the E. coli orthologue, this data also allows us to propose a molecular mechanism of lipid transport by the MLA system.
2399-3642
Mann, Daniel
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Fan, Junping
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Somboon, Kamolrat
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Farrell, Daniel P.
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Muenks, Andrew
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Tzokov, Svetomir B.
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DiMaio, Frank
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Khalid, Syma
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Miller, Samuel I.
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Bergeron, Julien R. C.
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Mann, Daniel
53b437a1-741f-4ca8-9dad-1fd9dc3f1f81
Fan, Junping
cebc3ddc-6ff9-4f8f-b67c-fefe044aa96f
Somboon, Kamolrat
78095e59-bba0-4a24-9aeb-ea1e1121da89
Farrell, Daniel P.
7952843b-f626-463b-ae6c-1fc3cd7dcabf
Muenks, Andrew
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Tzokov, Svetomir B.
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DiMaio, Frank
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Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Miller, Samuel I.
da42ddc9-0221-4991-8460-196cb5362da8
Bergeron, Julien R. C.
86ea7ddb-b5ae-4a34-a7f1-4008cd4415c6

Mann, Daniel, Fan, Junping, Somboon, Kamolrat, Farrell, Daniel P., Muenks, Andrew, Tzokov, Svetomir B., DiMaio, Frank, Khalid, Syma, Miller, Samuel I. and Bergeron, Julien R. C. (2021) Structure and lipid dynamics in the maintenance of lipid asymmetry inner membrane complex of A. baumannii. Communications Biology, 4 (1), [817]. (doi:10.1038/s42003-021-02318-4).

Record type: Article

Abstract

Multi-resistant bacteria are a major threat in modern medicine. The gram-negative coccobacillus Acinetobacter baumannii currently leads the WHO list of pathogens in critical need for new therapeutic development. The maintenance of lipid asymmetry (MLA) protein complex is one of the core machineries that transport lipids from/to the outer membrane in gram-negative bacteria. It also contributes to broad-range antibiotic resistance in several pathogens, most prominently in A. baumannii. Nonetheless, the molecular details of its role in lipid transport has remained largely elusive. Here, we report the cryo-EM maps of the core MLA complex, MlaBDEF, from the pathogen A. baumannii, in the apo-, ATP- and ADP-bound states, revealing multiple lipid binding sites in the cytosolic and periplasmic side of the complex. Molecular dynamics simulations suggest their potential trajectory across the membrane. Collectively with the recently-reported structures of the E. coli orthologue, this data also allows us to propose a molecular mechanism of lipid transport by the MLA system.

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MLA manuscript_final_v3_JB2 - Accepted Manuscript
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Accepted/In Press date: 27 May 2021
Published date: 29 June 2021
Additional Information: Funding Information: We are thankful for financial support through BBSRC project BB/R019061/1. We acknowledge Diamond Light Source for access and support of the cryo-EM facilities at the UK’s national Electron Bio-imaging Centre (eBIC) (under proposal EM-19832). We thank Emma Hasketh and Rebecca Thompson from the Astbury Centre for Structural Molecular Biology Leeds for support during measurements. We acknowledge support from LonCEM, King’s College London during measurements. The University of Sheffield FoS cryo-EM facility was used for grid preparation and optimization. We are grateful to Justin Kollman for help with the initial stages of this project. We acknowledge the use of the ARCHER supercomputer via HECBioSim, funded through EPSRC project EP/R029407/1, and the use of the IRIDIS High Performance Computing Facility at the University of Southampton. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

Identifiers

Local EPrints ID: 450333
URI: http://eprints.soton.ac.uk/id/eprint/450333
ISSN: 2399-3642
PURE UUID: 91208585-d31b-4532-8edb-0eda40f961f9
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

Catalogue record

Date deposited: 23 Jul 2021 16:30
Last modified: 26 Nov 2021 02:52

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Contributors

Author: Daniel Mann
Author: Junping Fan
Author: Kamolrat Somboon
Author: Daniel P. Farrell
Author: Andrew Muenks
Author: Svetomir B. Tzokov
Author: Frank DiMaio
Author: Syma Khalid ORCID iD
Author: Samuel I. Miller
Author: Julien R. C. Bergeron

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