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

Tang, Xiaodi, Chang, Shenghai, Qiao, Wen, Luo, Qinghua, Chen, Yuejia, Jia, Zhiying, Coleman, James, Zhang, Ke, Wang, Ting, Zhang, Zhibo, Zhang, Changbin, Zhu, Xiaofeng, Wei, Xiawei, Dong, Changjiang, Zhang, Xing and Dong, Haohao (2021) Structural insights into outer membrane asymmetry maintenance in Gram-negative bacteria by MlaFEDB. Nature Structural & Molecular Biology, 28 (1). pp. 81-91. ISSN 1545-9993

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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.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 17 Feb 2021 13:04
Last Modified: 13 May 2021 16:04
URI: https://ueaeprints.uea.ac.uk/id/eprint/79271
DOI: 10.1038/s41594-020-00532-y

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