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Structural insight into outer membrane asymmetry maintenance of Gram-negative bacteria by the phospholipid transporter MlaFEDB

By Xiaodi Tang, Shenghai Chang, Wen Qiao, Qinghua Luo, Yuejia Chen, Zhiying Jia, James Coleman, Ke Zhang, Ting Wang, Zhibo Zhang, Changbin Zhang, Xiaofeng Zhu, Xiawei Wei, Changjiang Dong, Xing Zhang, Haohao Dong

Posted 05 Jun 2020
bioRxiv DOI: 10.1101/2020.06.04.133611

The asymmetric outer membrane (OM) of Gram-negative bacteria serves as the first line of defense against cytotoxic substances such as antibiotics. The Mla pathway is known to maintain the lipid asymmetry of the OM by transporting phospholipids between the inner and outer membranes. Six Mla proteins MlaFEDBCA are involved, with the ABC transporter MlaFEDB acts through a mechanism yet to be elucidated. Here we determine cryo-EM structures of MlaFEDB in apo, phospholipid-, ADP- or AMP-PNP-bound state to 3.3-3.75 Angstrom resolution and establish a proteoliposome-based transport system containing MlaFEDB, MlaC and MlaA/OmpF to reveal the transport direction of phospholipids. Mutagenetic in vitro transport assays and in vivo sensitivity assays reveal functional residues which recognize and transport phospholipids as well as regulate the activity and structural stability of the MlaFEDB complex. Our work provides molecular basis for understanding the mechanism of the Mla pathway which could be targeted for antimicrobial drug development. ### Competing Interest Statement The authors have declared no competing interest.

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