Structural insight into outer membrane asymmetry maintenance of Gram-negative bacteria by the phospholipid transporter MlaFEDB
Structural insight into outer membrane asymmetry maintenance of Gram-negative bacteria by the phospholipid transporter MlaFEDB
The asymmetric phospholipid 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 ? 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.
Jia Zhiying、Tang Xiaodi、Wang Ting、Zhang Zhibo、Dong Changjiang、Chen Yuejia、Zhu Xiaofeng、Luo Qinghua、Zhang Changbin、Zhang Xing、Dong Haohao、Coleman James、Zhang Ke、Wei Xiawei、Chang Shenghai、Qiao Wen
Department of Pathology of Sir Run Run Shaw Hospital, and Department of Biophysics, Zhejiang University, School of Medicine||Center of Cryo Electron Microscopy, Zhejiang UniversityState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyBiomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research ParkState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy||College of Life Science, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyDepartment of Pathology of Sir Run Run Shaw Hospital, and Department of Biophysics, Zhejiang University, School of Medicine||Center of Cryo Electron Microscopy, Zhejiang UniversityState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyBiomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research ParkState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of BiotherapyDepartment of Pathology of Sir Run Run Shaw Hospital, and Department of Biophysics, Zhejiang University, School of Medicine||Center of Cryo Electron Microscopy, Zhejiang UniversityState Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy
分子生物学微生物学生物化学
Jia Zhiying,Tang Xiaodi,Wang Ting,Zhang Zhibo,Dong Changjiang,Chen Yuejia,Zhu Xiaofeng,Luo Qinghua,Zhang Changbin,Zhang Xing,Dong Haohao,Coleman James,Zhang Ke,Wei Xiawei,Chang Shenghai,Qiao Wen.Structural insight into outer membrane asymmetry maintenance of Gram-negative bacteria by the phospholipid transporter MlaFEDB[EB/OL].(2025-03-28)[2025-07-16].https://www.biorxiv.org/content/10.1101/2020.06.04.133611.点此复制
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