Pore Formation by Cholesterol Dependent Cytolysins

胆固醇依赖性溶细胞素形成孔

基本信息

项目摘要

Our work over the course of nearly 25 years of this grant have revealed insights onto the pore-forming mechanism of the cholesterol-dependent cytolysins (CDCs), which have laid the foundations to understand the basis by which this large class of toxins make the transition from soluble monomers to large oligomeric membrane-embedded pore complexes. In the next 5 years of the merit award we propose to address three specific aims, which will continue our work on the CDCs but will also open up new major fields of research in related areas. In the first aim we will address outstanding issues in the mechanism of the CDC pore-forming mechanism. The first of these is to understand how the β-barrel pore assembles and inserts into the membrane bilayer. This is a question that applies to all β-barrel pore-forming proteins but is fraught with complicating thermodynamic factors. Using our previous discoveries of the transition state barriers to pore formation and the ability to change the nature of the β-hairpins we will determine the mechanism of β-barrel assembly and membrane insertion. These studies will also address a contentious issue in the CDC-mechanism, which is whether incomplete oligomers (rather than complete rings) can insert a partial β-barrel into the membrane. In this aim we will also reassess the basis by which the listeriolysin 0 pH sensor functions, as we have recent published data and preliminary studies, which suggest that our original hypothesis made in 1995 is not the mechanism of pH sensing. In the second aim we plan to pursue the study of the CDC-like (CDCL) proteins that we have determined to be ancient relatives of the CDCs (perhaps the forerunners of the CDCs), the genes for which are widespread in numerous bacterial species (>300 so far) from at least 6 different phyla, as well as a few species of diatoms and fungi. Our primary goals are to (1) understand the pore-forming mechanism of these toxins, as some preliminary data suggest there are some fundamental differences with the CDCs, and (2) to identify the prokaryotic and/or eukaryotic targets of several of these proteins isolated from species from the oral and intestinal human microbiomes and from terrestrial environments, as none of the CDCL binding domains exhibit any similarity to the canonical binding domain of the CDCs. In the third aim we plan to study the mechanism of bacterial killing by a novel class of anti-bacterial toxins that are produced by a few species of the Provotella and Bacteroides found in the oral and intestinal microbiome of humans. Our preliminary studies suggest that they are proteolytically-activated toxins that form higher order complexes (possibly pore-forming toxins), which target various species of bacteria. Our preliminary studies suggest that they are a unique class of antibacterial toxin, as there are no known class of prokaryotic or eukaryotic toxins that exhibit any similarity to the primary structure of these toxins.
我们在近 25 年的资助过程中所做的工作揭示了对成孔机制的见解 胆固醇依赖性溶细胞素 (CDC) 的研究,为理解胆固醇依赖性溶细胞素 (CDC) 的基础奠定了基础 这一大类毒素从可溶性单体转变为大型寡聚膜嵌入 孔隙复合体。在未来 5 年的优异奖中,我们建议实现三个具体目标,这将 继续我们在疾病预防控制中心的工作,但也将在相关领域开辟新的主要研究领域。在第一个目标中 我们将解决CDC成孔机制中的突出问题。其中第一个是 了解 β-桶孔如何组装并插入膜双层。这是一个适用的问题 适用于所有 β-桶成孔蛋白,但充满了复杂的热力学因素。使用我们之前的 发现孔形成的过渡态障碍以及改变 β-发夹性质的能力 我们将确定β-桶组装和膜插入的机制。这些研究还将解决 CDC机制中存在争议的问题是是否是不完整的低聚物(而不是完整的环) 可以将部分β-桶插入膜中。为此,我们还将重新评估李斯特菌溶血素的基础 0 pH 传感器功能,因为我们最近发布的数据和初步研究表明我们最初的 1995 年提出的假设不是 pH 传感机制。在第二个目标中,我们计划继续研究 我们已确定类 CDC (CDCL) 蛋白是 CDC 的远亲(也许是 CDC 的前身),其基因广泛存在于自 至少有 6 个不同的门,以及几种硅藻和真菌。我们的主要目标是 (1) 了解 这些毒素的成孔机制,一些初步数据表明存在一些基本原理 与 CDC 的差异,以及 (2) 鉴定其中几种蛋白质的原核和/或真核靶标 从人类口腔和肠道微生物组以及陆地环境中的物种中分离出来,因为没有 CDCL 结合域与 CDC 的规范结合域表现出任何相似性。在第三个目标中 我们计划研究一类新型抗菌毒素杀死细菌的机制,这些毒素是由细菌产生的。 在人类口腔和肠道微生物组中发现的普罗沃菌属和拟杆菌属很少。我们的 初步研究表明它们是蛋白水解激活的毒素,形成高级复合物 (可能是成孔毒素),针对各种细菌。我们的初步研究表明他们 是一类独特的抗菌毒素,因为没有已知的原核或真核毒素表现出 与这些毒素的一级结构有任何相似之处。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)

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Rodney K. Tweten其他文献

Molecular cloning and expression of gene fragments from corynebacteriophage beta encoding enzymatically active peptides of diphtheria toxin
编码白喉毒素酶活性肽的β棒状噬菌体基因片段的分子克隆和表达
  • DOI:
    10.1128/jb.156.2.680-685.1983
  • 发表时间:
    1983
  • 期刊:
  • 影响因子:
    3.2
  • 作者:
    Rodney K. Tweten;Robert J Collier
  • 通讯作者:
    Robert J Collier
Cloning and expression in Escherichia coli of the perfringolysin O (theta-toxin) gene from Clostridium perfringens and characterization of the gene product
产气荚膜梭菌产气荚膜溶血素 O(theta 毒素)基因在大肠杆菌中的克隆和表达以及基因产物的表征
  • DOI:
    10.1128/iai.56.12.3228-3234.1988
  • 发表时间:
    1988
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Rodney K. Tweten
  • 通讯作者:
    Rodney K. Tweten
Nucleotide sequence of the gene for perfringolysin O (theta-toxin) from Clostridium perfringens: significant homology with the genes for streptolysin O and pneumolysin
产气荚膜梭菌产气荚膜溶血素 O(theta 毒素)基因的核苷酸序列:与链球菌溶血素 O 和肺炎球菌溶血素基因显着同源
  • DOI:
    10.1128/iai.56.12.3235-3240.1988
  • 发表时间:
    1988
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Rodney K. Tweten
  • 通讯作者:
    Rodney K. Tweten
Purification and properties of the carbonic anhydrase of Rhodospirillum rubrum
  • DOI:
    10.1007/bf00413010
  • 发表时间:
    1984-06-01
  • 期刊:
  • 影响因子:
    2.600
  • 作者:
    Steven R. Gill;Paula J. Fedorka-Cray;Rodney K. Tweten;Bayard P. Sleeper
  • 通讯作者:
    Bayard P. Sleeper

Rodney K. Tweten的其他文献

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{{ truncateString('Rodney K. Tweten', 18)}}的其他基金

Pore Formation by Cholesterol Dependent Cytolysins
胆固醇依赖性溶细胞素形成孔
  • 批准号:
    10584602
  • 财政年份:
    2021
  • 资助金额:
    $ 47.52万
  • 项目类别:
Pore Formation by Cholesterol Dependent Cytolysins
胆固醇依赖性溶细胞素形成孔
  • 批准号:
    10049602
  • 财政年份:
    2021
  • 资助金额:
    $ 47.52万
  • 项目类别:
A Novel Cholesterol-Dependent Cytolysin Receptor
一种新型胆固醇依赖性溶细胞素受体
  • 批准号:
    6860745
  • 财政年份:
    2005
  • 资助金额:
    $ 47.52万
  • 项目类别:
A Novel Cholesterol-Dependent Cytolysin Receptor
一种新型胆固醇依赖性溶细胞素受体
  • 批准号:
    7172320
  • 财政年份:
    2005
  • 资助金额:
    $ 47.52万
  • 项目类别:
A Novel Cholesterol-Dependent Cytolysin Receptor
一种新型胆固醇依赖性溶细胞素受体
  • 批准号:
    7007618
  • 财政年份:
    2005
  • 资助金额:
    $ 47.52万
  • 项目类别:
A Novel Cholesterol-Dependent Cytolysin Receptor
一种新型胆固醇依赖性溶细胞素受体
  • 批准号:
    7324132
  • 财政年份:
    2005
  • 资助金额:
    $ 47.52万
  • 项目类别:
DOMAIN MAPPING CLOSTRIDIUM PERFRINGENS THETA TOXIN
产气荚膜梭菌 Theta 毒素的结构域图谱
  • 批准号:
    2004242
  • 财政年份:
    1997
  • 资助金额:
    $ 47.52万
  • 项目类别:
Pore Formation by Cholesterol Dependent Cytolysins
胆固醇依赖性溶细胞素形成孔
  • 批准号:
    8121859
  • 财政年份:
    1997
  • 资助金额:
    $ 47.52万
  • 项目类别:
DOMAIN MAPPING CLOSTRIDIUM PERFRINGENS THETA TOXIN
产气荚膜梭菌 Theta 毒素的结构域图谱
  • 批准号:
    2672473
  • 财政年份:
    1997
  • 资助金额:
    $ 47.52万
  • 项目类别:
DOMAIN MAPPING CLOSTRIDIUM PERFRINGENS THETA TOXIN
产气荚膜梭菌 Theta 毒素的结构域图谱
  • 批准号:
    6169992
  • 财政年份:
    1997
  • 资助金额:
    $ 47.52万
  • 项目类别:

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New technologies for targeted delivery of anti-bacterial agents
抗菌药物靶向递送新技术
  • 批准号:
    1654774
  • 财政年份:
    2015
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    $ 47.52万
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Targeting bacterial phosphatases for novel anti-bacterial agents.
针对细菌磷酸酶的新型抗菌剂。
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Targeting bacterial phosphatases for novel anti-bacterial agents.
针对细菌磷酸酶的新型抗菌剂。
  • 批准号:
    8298885
  • 财政年份:
    2012
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