TY - JOUR
T1 - Structure and lipid dynamics in the maintenance of lipid asymmetry inner membrane complex of A. baumannii
AU - Mann, Daniel
AU - Fan, Junping
AU - Somboon, Kamolrat
AU - Farrell, Daniel P
AU - Muenks, Andrew
AU - Tzokov, Svetomir B
AU - DiMaio, Frank
AU - Khalid, Syma
AU - Miller, Samuel I
AU - Bergeron, Julien R C
N1 - 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.
PY - 2021/6/29
Y1 - 2021/6/29
N2 - 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.
AB - 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.
KW - Acinetobacter baumannii/chemistry
KW - Adenosine Triphosphate/chemistry
KW - Binding Sites
KW - Cell Membrane/chemistry
KW - Cryoelectron Microscopy
KW - Membrane Lipids/chemistry
KW - Molecular Dynamics Simulation
UR - http://www.scopus.com/inward/record.url?scp=85109050587&partnerID=8YFLogxK
U2 - 10.1038/s42003-021-02318-4
DO - 10.1038/s42003-021-02318-4
M3 - Article
C2 - 34188171
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 817
ER -