Synergy between acid stress chaperones HdeA and HdeB with clients and their key sites of activity

酸应激伴侣 HdeA 和 HdeB 与客户及其关键活动位点之间的协同作用

基本信息

项目摘要

PROJECT SUMMARY / ABSTRACT Background. Pathogenic bacteria must travel through the highly acidic environment of the stomach before they can reach and infect the intestines. The stomach is therefore an important barricade which helps to kill many bacteria before they can cause illness. In some of the most infectious bacteria, however, ATP- independent chaperones HdeA and HdeB play major roles in aiding bacterial survival at low pH. Their job is to protect other proteins from misfolding and aggregating as the cell transitions through the harsh environment of the stomach and into the neutral environment of the intestines. HdeB is active at intermediate pH values, while HdeA functions at the low pH typical of stomach acid. Although there are various models available to explain the interplay between the two chaperones, it is still unclear which, if any, is correct. Specific aims. The goal of the proposed work is to use NMR spectroscopy and other biophysical techniques to pursue an in-depth investigation of the apparently synergistic mechanism by which the two chaperone proteins operate and to probe the roles of specific residues that trigger or modify the activation of HdeA or HdeB. Aim #1 is to examine the roles and interactions of HdeA and HdeB with chaperone clients as a function of pH. Isotopic labeling and the unique properties of NMR spectroscopy will be employed to monitor each protein individually within a mixture of HdeA, HdeB and a client protein, thereby providing different vantage points to obtain unprecedented detail. Aim #2 is to probe sites of chaperone activation and stability in HdeA and HdeB using targeted mutations. Here, a variety of techniques will be used to closely assess segments of each protein that have been linked to essential roles in function and/or activation, including a key tryptophan in the dimer interface of HdeB and the disulfide bond in HdeA, which helps to maintain the semi-folded structure believed to be important to its chaperone function. Health-related significance. Dysentery, caused by intestinal infection by pathogenic bacteria, kills at least 350,000 people per year worldwide. If we can elucidate the individual and collective roles of HdeA and HdeB in the presence of client proteins, as well as the mechanistic importance of specific residues or regions, we can better understand how these acid-stress chaperones help bacteria survive under extreme conditions. Improved understanding can inform researchers designing vaccines or other therapeutics that can disable the activities of HdeA and HdeB and thereby weaken the infectivity of these pathogenic bacteria.
项目摘要/摘要

项目成果

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KARIN A CROWHURST其他文献

KARIN A CROWHURST的其他文献

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{{ truncateString('KARIN A CROWHURST', 18)}}的其他基金

Synergy between acid stress chaperones HdeA and HdeB with clients and their key sites of activity
酸应激伴侣 HdeA 和 HdeB 与客户及其关键活动位点之间的协同作用
  • 批准号:
    10334239
  • 财政年份:
    2016
  • 资助金额:
    $ 10.88万
  • 项目类别:
Synergy between acid stress chaperones HdeA and HdeB with clients and their key sites of activity
酸应激伴侣 HdeA 和 HdeB 与客户及其关键活动位点之间的协同作用
  • 批准号:
    10681291
  • 财政年份:
    2016
  • 资助金额:
    $ 10.88万
  • 项目类别:
In vitro and in-cell investigation of the acid-stress chaperone HdeA
酸应激伴侣 HdeA 的体外和细胞内研究
  • 批准号:
    8999898
  • 财政年份:
    2016
  • 资助金额:
    $ 10.88万
  • 项目类别:
In vitro and in-cell investigation of the acid-stress chaperone HdeA
酸应激伴侣 HdeA 的体外和细胞内研究
  • 批准号:
    9249639
  • 财政年份:
    2016
  • 资助金额:
    $ 10.88万
  • 项目类别:
Investigating protein dynamics in NT-4/5 and TrkB receptor interactions
研究 NT-4/5 和 TrkB 受体相互作用的蛋白质动力学
  • 批准号:
    7939442
  • 财政年份:
    2010
  • 资助金额:
    $ 10.88万
  • 项目类别:
Investigating protein dynamics in NT-4/5 and TrkB receptor interactions
研究 NT-4/5 和 TrkB 受体相互作用的蛋白质动力学
  • 批准号:
    8274631
  • 财政年份:
    2010
  • 资助金额:
    $ 10.88万
  • 项目类别:
Investigating protein dynamics in NT-4/5 and TrkB receptor interactions
研究 NT-4/5 和 TrkB 受体相互作用的蛋白质动力学
  • 批准号:
    8098224
  • 财政年份:
    2010
  • 资助金额:
    $ 10.88万
  • 项目类别:

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