Structural basis for outer membrane lipopolysaccharide insertion

摘要

Haohao Dong等人和Shuai Qiao等人发表了分别来自细菌Salmonella typhimurium和Shigella flexneri的脂多糖运输蛋白LptD和LptE之间所形成的复合物的X-射线晶体结构。这两篇论文报告了LptD-LptE复合物的一个独特的二蛋白plug-and-barrel架构,它显示了细胞壁脂多糖被输送和插入到革兰氏阴性细菌外膜的外小叶中去的机制。除了提供关于外膜生物生成的性质的新细节外,这项工作还将提供对以细菌外膜为目标的新抗生素策略的设计有用的数据,这种策略是在防治多药物抗性病原体的工作中非吊需要的。%Lipopolysaccharide (LPS) is essential for most Gram-negative bacteria and has crucial roles in protection of the bacteria from harsh environments and toxic compounds, including antibiotics. Seven LPS transport proteins (that is, LptA-LptG) form a trans-envelope protein complex responsible for the transport of LPS from the inner membrane to the outer membrane, the mechanism for which is poorly understood. Here we report the first crystal structure of the unique integral membrane LPS translocon LptD-LptE complex. LptD forms a novel 26-stranded β-barrel, which is to our knowledge the largest β-barrel reported so far. LptE adopts a roll-like structure located inside the barrel of LptD to form an unprecedented two-protein 'barrel and plug' architecture. The structure, molecular dynamics simulations and functional assays suggest that the hydrophilic O-antigen and the core oligosaccharide of the LPS may pass through the barrel and the lipid A of the LPS may be inserted into the outer leaflet of the outer membrane through a lateral opening between strands β1 and β26 of LptD. These findings not only help us to understand important aspects of bacterial outer membrane biogenesis, but also have significant potential for the development of novel drugs against multi-drug resistant pathogenic bacteria.