【译文】全球一半的人口慢性地感染幽门螺旋杆菌,从而引发胃炎、胃溃疡,增加胃腺癌的发病率。幽门螺旋杆菌的质子门控尿素通道即HP UREI是保证其生存在胃酸性环境中必不可少的。通道在中性pH条件下关闭,在酸性pH条件下打开,并允许尿素迅速进入细胞质脲酶。脲酶生产的NH3和CO2,中和进入的质子,使细胞周质pH维持在6.1左右,即使处于胃液pH低于2.0的条件下。此项研究揭示了HpUreI UREI 的结构,暴露了围绕着有序脂质双层中心组装在六聚体环的六个原体。每个原体包围着由六个跨膜螺旋束扭曲所形成的通道。螺旋束是先前未观察到的褶皱,包括两个螺旋发夹重复三次围绕通道的中心轴,但没有反向重复序列的哺乳动物型尿素转运。通道和原体均包含AmiS/UreI超家族保守的残基,显示了此家族通道结构和寡聚状态的保守性。整个通道主要由芳族或脂肪族侧链构成,中间有两个连续的收缩位点。与硫脲相比,细胞质中收缩位点Trp 153的突变降低了尿素的灵敏性,这表明与Trp 153的溶质相互作用也贡献了其特异性。这种前未观测到的六聚体通道结构为原核生物和古细菌中提供了一种尿素及其他小酰胺溶质的渗透新模式。


[Title]: Structure of the proton-gated urea channel from the gastric pathogen Helicobacter pylori

[Authors]:David Strugatsky,1, 7 Reginald McNulty,2, 7, 8 Keith Munson,1, 7 Chiung-Kuang Chen,2 S. Michael Soltis,3 George Sachs1 & Hartmut Luecke2, 4, 5, 6

[Abstract]Half the world’s population is chronically infected with Helicobacter pylori, causing gastritis, gastric ulcers and an increased incidence of gastric adenocarcinoma. Its proton-gated inner-membrane urea channel, HpUreI, is essential for survival in the acidic environment of the stomach. The channel is closed at neutral pH and opens at acidic pH to allow the rapid access of urea to cytoplasmic urease. Urease produces NH3 and CO2, neutralizing entering protons and thus buffering the periplasm to a pH of roughly 6.1 even in gastric juice at a pH below 2.0. Here we report the structure of HpUreI, revealing six protomers assembled in a hexameric ring surrounding a central bilayer plug of ordered lipids. Each protomer encloses a channel formed by a twisted bundle of six transmembrane helices. The bundle defines a previously unobserved fold comprising a two-helix hairpin motif repeated three times around the central axis of the channel, without the inverted repeat of mammalian-type urea transporters. Both the channel and the protomer interface contain residues conserved in the AmiS/UreI superfamily, suggesting the preservation of channel architecture and oligomeric state in this superfamily. Predominantly aromatic or aliphatic side chains line the entire channel and define two consecutive constriction sites in the middle of the channel. Mutation of Trp 153 in the cytoplasmic constriction site toAla or Phe decreases the selectivity for urea in comparison with thiourea, suggesting that solute interaction with Trp 153 contributes specificity. The previously unobserved hexameric channel structure described here provides a new model for the permeation of urea and other small amide solutes in prokaryotes and archaea.


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