Role of a novel auto-protease domain in antibacterial toxin delivery

新型自体蛋白酶结构域在抗菌毒素递送中的作用

基本信息

批准号：
10372140
负责人：
Celia Goulding
金额：
$ 19.53万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372140
关键词：
Acinetobacter Amino Acid Sequence Anti-Bacterial Agents Architecture Asparagine Bacteria Bacterial Genome Binding Biochemical Biochemistry Burkholderia C-terminal Cell surface Cells Chimera organism Complex Crystallization Crystallography Cytoplasm Cytosol Databases Engineering Enterobacteriaceae Environment Escherichia coli Family Gene Cluster Gram-Negative Bacteria Growth Immunity Individual LYN gene Left Lyase Mediating Membrane Microbe Modeling Molecular Molecular Genetics Mutate Neisseria Pathway interactions Peptide Hydrolases Peptides Protease Domain Protein Secretion Proteins Pseudomonas Reporting Research Role Siblings Site-Directed Mutagenesis Structural Models Structure System Testing Thin Filament Toxin Vertebral column Work antimicrobial functional plasticity human pathogen inhibitor insight new technology novel novel strategies pathogen pathogenic bacteria periplasm protein aminoacid sequence receptor receptor binding structural biology

Acinetobacter Amino Acid Sequence Anti-Bacterial Agents Architecture Asparagine Bacteria Bacterial Genome Binding Biochemical Biochemistry Burkholderia C-terminal Cell surface Cells Chimera organism Complex Crystallization Crystallography Cytoplasm Cytosol Databases Engineering Enterobacteriaceae Environment Escherichia coli Family Gene Cluster Gram-Negative Bacteria Growth Immunity Individual LYN gene Left Lyase Mediating Membrane Microbe Modeling Molecular Molecular Genetics Mutate Neisseria Pathway interactions Peptide Hydrolases Peptides Protease Domain Protein Secretion Proteins Pseudomonas Reporting Research Role Siblings Site-Directed Mutagenesis Structural Models Structure System Testing Thin Filament Toxin Vertebral column Work antimicrobial functional plasticity human pathogen inhibitor insight new technology novel novel strategies pathogen pathogenic bacteria periplasm protein aminoacid sequence receptor receptor binding structural biology

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项目摘要

Project summary Contact-dependent growth inhibition (CDI) is an important mechanism of inter-bacterial competition found in a wide variety of Gram-negative bacteria, including many important human pathogens. CDI is mediated by the CdiB/CdiA family of two-partner secretion proteins, which are thought to assemble as a binary complex on the cell surface. CdiA forms a thin filament to projects away from the inhibitor cell to bind to receptors on susceptible bacteria. After binding receptor, CdiA delivers its C-terminal toxin domain (CdiA-CT) into the target cell. CDI systems also encode CdiI immunity proteins, which specifically bind to the CdiA-CT and neutralize toxin activity to protect the cell from auto-inhibition. CdiA-CT/CdiI sequences are extraordinarily variable, with >130 distinct toxin/immunity protein sequence types recognized in bacterial genomes. CdiA-CT toxins are modular and can be exchanged between CdiA proteins to generate functional chimeras. These observations indicate that many different kinds of toxic cargo can be delivered into the cytoplasm of target bacteria. This application seeks to determine the molecular and structural underpinnings that enable this remarkable functional plasticity. We will use a combination of molecular genetic, biochemical and structural approaches to gain insight into the functional interactions between the constituent domains of CdiA. This research will significantly increase our mechanistic understanding of CdiA function and could inform novel strategies for antimicrobial therapy.

项目摘要接触依赖性生长抑制（CDI）是细菌间竞争的重要机制在各种革兰氏阴性细菌中发现，包括许多重要的人类病原体。 CDI是由CDIB/CDIA家族的两伴侣分泌蛋白介导的蛋白质，被认为是二进制的在细胞表面上复杂。 CDIA形成了远离抑制剂细胞的项目，以结合易感细菌的受体。结合受体后，CDIA提供其C末端毒素结构域（CDIA-CT）进入目标细胞。 CDI系统还编码CDII免疫蛋白，该蛋白特别结合了CDIA-CT 并中和毒素活性以保护细胞免受自身抑制作用。 CDIA-CT/CDII序列非常可变，> 130个不同的毒素/免疫蛋白序列类型在细菌基因组中识别。 CDIA-CT 毒素是模块化的，可以在CDIA蛋白之间交换以产生功能性嵌合体。这些观察结果表明，许多不同种类的有毒货物可以输送到靶标的细胞质中细菌。该应用程序旨在确定使这一点的分子和结构基础显着的功能可塑性。我们将结合分子遗传，生化和结构方法可以深入了解CDIA组成域之间的功能相互作用。这研究将大大提高我们对CDIA功能的机械理解，并可以为新颖抗菌治疗策略。