Crystallographic analysis of Neisseria meningitidis PorB extracellular loops potentially implicated in TLR2 recognition
Crystallographic analysis of Neisseria meningitidis PorB extracellular loops potentially implicated in TLR2 recognition
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DOI：
10.1016/j.jsb.2013.12.006
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发表时间：
2014-03-01
影响因子：
3
通讯作者：
Tanabe, Mikio
中科院分区：
文献类型：
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作者：
Kattner, Christof;Toussi, Deana N.;Tanabe, Mikio
在所有奈瑟亚科物种中，脑膜炎奈瑟菌和淋病奈瑟菌是人类仅有的病原体，分别是细菌性脑膜炎和淋病的病原体。PorB是一种泛奈瑟亚科三聚孔蛋白，通过Toll样受体2(TLR2)介导的信号转导，介导基本分子在细菌外膜上的扩散运输，也被认为可以激活宿主的先天免疫。PorB与TLR2结合的分子机制尚不清楚，但已假设静电相互作用有助于配体/受体结合。在可能与TLR2结合有关的PorB表面暴露环中的菌株特异性序列差异性，可能解释了来自共生的乳链球菌和病原体脑膜炎奈瑟菌的PorB同源物在体外TLR2介导的细胞激活方面的差异。在这里，我们报告了脑膜炎奈瑟氏菌B群8765株的PorB基因的比较结构分析(序列与脑膜炎奈瑟菌W135群的PorB有63%的同源性)和一个突变体，在该突变体中，细胞外环7中的氨基酸替换导致体外TLR2依赖活性显著降低。我们观察到，这种突变既改变了环的构象，又导致了表面静电电荷的急剧变化，这两者都可能影响TLR2的识别和信号转导。(C)2013 Elsevier Inc.保留所有权利。
Among all Neisseriae species, Neisseria meningitidis and Neisseria gonorrhoeae are the only human pathogens, causative agents of bacterial meningitis and gonorrhoea, respectively. PorB, a pan-Neisseriae trimeric porin that mediates diffusive transport of essential molecules across the bacterial outer membrane, is also known to activate host innate immunity via Toll-like receptor 2 (TLR2)-mediated signaling. The molecular mechanism of PorB binding to TLR2 is not known, but it has been hypothesized that electrostatic interactions contribute to ligand/receptor binding. Strain-specific sequence variability in the surface-exposed loops of PorB which are potentially implicated in TLR2 binding, may explain the difference in TLR2-mediated cell activation in vitro by PorB homologs from the commensal Neisseriae lactamica and the pathogen N. meningitidis. Here, we report a comparative structural analysis of PorB from N. meningitidis serogroup B strain 8765 (63% sequence homology with PorB from N. meningitidis serogroup W135) and a mutant in which amino acid substitutions in the extracellular loop 7 lead to significantly reduced TLR2-dependent activity in vitro. We observe that this mutation both alters the loop conformation and causes dramatic changes of electrostatic surface charge, both of which may affect TLR2 recognition and signaling. (C) 2013 Elsevier Inc. All rights reserved.