Dong Haohao, Zhang Zhengyu, Tang Xiaodi, Huang Shihai, Li Huanyu, Peng Bo, Dong Changjiang
Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY, UK.
Sci Rep. 2016 Aug 4;6:30815. doi: 10.1038/srep30815.
The outer membrane (OM) of Gram-negative bacteria is a unique asymmetric lipid bilayer in which the outer leaflet is composed of lipopolysaccharide (LPS) and the inner leaflet is formed by glycerophospholipid (GPL). The OM plays a fundamental role in protecting Gram-negative bacteria from harsh environments and toxic compounds. The transport and assembly pathways for phospholipids of bacterial OM are unknown. Cardiolipin (CL) plays an important role in OM biogenesis and pathogenesis, and the inner membrane (IM) protein PbgA, containing five transmembrane domains and a globular domain in periplasm has been recently identified as a CL transporter from the IM to the OM with an unknown mechanism. Here we present the first two crystal structures of soluble periplasmic globular domain of PbgA from S. typhimurium and E. coli, which revealed that the globular domains of PbgA resemble the structures of the arylsulfatase protein family and contains a novel core hydrophobic pocket that may be responsible for binding and transporting CLs. Our structural and functional studies shed an important light on the mechanism of CL transport in Gram-negative bacteria from the IM to the OM, which offers great potential for the development of novel antibiotics against multi-drug resistant bacterial infections.
革兰氏阴性菌的外膜是一种独特的不对称脂质双层膜，其中外层由脂多糖（LPS）组成，内层由甘油磷脂（GPL）形成。外膜在保护革兰氏阴性菌免受恶劣环境和有毒化合物的侵害方面起着至关重要的作用。细菌外膜磷脂的运输和组装途径尚不清楚。心磷脂（CL）在外膜生物合成和发病机制中起重要作用，内膜（IM）蛋白PbgA含有五个跨膜结构域和一个位于周质的球状结构域，最近被鉴定为一种从内膜到外膜的CL转运蛋白，但其机制尚不清楚。在这里，我们展示了鼠伤寒沙门氏菌和大肠杆菌中PbgA可溶性周质球状结构域的前两个晶体结构，这些结构表明PbgA的球状结构域类似于芳基硫酸酯酶蛋白家族的结构，并包含一个可能负责结合和运输心磷脂的新型核心疏水口袋。我们的结构和功能研究为革兰氏阴性菌中的心磷脂从内膜到外膜的运输机制提供了重要线索，这为开发针对多重耐药细菌感染的新型抗生素提供了巨大潜力。
