Structural insights into outer membrane asymmetry maintenance in Gram-negative bacteria by MlaFEDB.

Nature Structural & Molecular Biology
Xiaodi TangHaohao Dong

Abstract

The highly asymmetric outer membrane of Gram-negative bacteria functions in the defense against cytotoxic substances, such as antibiotics. The Mla pathway maintains outer membrane lipid asymmetry by transporting phospholipids between the inner and outer membranes. It comprises six Mla proteins, MlaFEDBCA, including the ABC transporter MlaFEDB, which functions via an unknown mechanism. Here we determine cryo-EM structures of Escherichia coli MlaFEDB in an apo state and bound to phospholipid, ADP or AMP-PNP to a resolution of 3.3-4.1 Å and establish a proteoliposome-based transport system that includes MlaFEDB, MlaC and MlaA-OmpF to monitor the transport direction of phospholipids. In vitro transport assays and in vivo membrane permeability assays combined with mutagenesis identify functional residues that not only recognize and transport phospholipids but also regulate the activity and structural stability of the MlaFEDB complex. Our results provide mechanistic insights into the Mla pathway, which could aid antimicrobial drug development.

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Citations

Dec 29, 2020·Nature Structural & Molecular Biology·Russell E Bishop
Mar 31, 2021·Nature Structural & Molecular Biology·Xiaodi TangHaohao Dong
Aug 21, 2021·Biochemical Society Transactions·Giedre RatkeviciuteTimothy J Knowles

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Methods Mentioned

BETA
fluorescence resonance
FRET
environmental stress
size-exclusion chromatography
pull down
size-exclusion
gel filtration
PCR
Assay

Software Mentioned

Phyre2
Phenix
Coot
RELION
MotionCor2
MolProbity
SerialEM
UCSF Chimera
Dali server

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