The contribution of novel cytidine deaminase regulatory systems to bacterial evolution
新型胞苷脱氨酶调节系统对细菌进化的贡献
基本信息
- 批准号:10339467
- 负责人:
- 金额:$ 57.87万
- 依托单位:
- 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:2021-02-05 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressBacteriaBacterial GenomeBacterial PhysiologyBacteriophagesBindingBiochemicalBiochemistryBioinformaticsBiologicalBiological ProcessBiologyCellsCellular biologyCessation of lifeCollaborationsCyclic GMPCytidine DeaminaseDefense MechanismsDisciplineDissectionEnterobacter cloacaeEnzymesEscherichia coliEukaryotaEvolutionFilamentGene ExpressionGenesGeneticGenetic studyGenomeGenomic IslandsHomeostasisIn VitroInfectionIslandLifeMicroscopyMutationN-terminalNamesNucleic AcidsNucleotidesOrganismOrthologous GenePeptidesPhosphotransferasesPhysiologyPlayProtein BiochemistryProteinsProteobacteriaPublicationsRecording of previous eventsRegulationResearchRoleSignal TransductionStructural ProteinStructureSystemTertiary Protein StructureTestingToxic effectTrans-ActivatorsTreesUntranslated RNAUrsidae FamilyVibrioVibrio choleraeViralVirus DiseasesWaterbaseclinically relevantdeoxycytidine deaminaseexperienceexperimental studygene functioninhibitormutantnoveloverexpressionpandemic diseasepathogenic bacteriapreventprotein complexsmall moleculestructural biologytoolvirtual
项目摘要
Project Summary: The current and 7th pandemic of Vibrio cholerae caused by the El Tor biotype encodes two
novel genetic islands called the Vibrio Seventh Pandemic Islands 1 and 2 (VSP-1 and VSP-2). Although
acquisition of these islands is proposed to be key to initiation of the 7th pandemic, the function of these genes
remains virtually unknown. The over-arching purpose of this proposal is to understand the function and regulation
of a novel bacterial cytidine deaminase (CDA) regulatory system that we have discovered is encoded on VSP-1
and in many other Proteobacteria. This new CDA regulatory system consists of the multi-domain protein we
named DcdV (deoxycytidine deaminase Vibrio) and its inhibitor named DifV (DcdV inhibitory factor Vibrio)
encoded in a 222 NT region 5’ of dcdV. These genes were first identified as our bioinformatic analysis indicated
that they significantly cooccur in bacterial genomes with the VSP-1 encoded DncV/CapV cyclic GMP-AMP phage
defense system that we previously discovered. Consistent with a potential role of DcdV-DifV to regulate phage
defense, expressing DcdV in the absence of difV causes cell filamentation and disruption of dNTP pools in V.
cholerae and Escherichia coli. Deoxycytidine deaminases (DCD) enzymes play critical roles in maintaining
nucleotide homeostasis, hypermutation, and viral defense in both bacteria and eukaryotes, but in numerous
respects, DcdV and its orthologs are quite different from any other previously studied DCDs. For example, all
previously described DCDs are single domain proteins, while DcdV has an associated N-terminal nucleotide
kinase (NK) domain that our genetic studies show is essential for DcdV activity. Furthermore, other DCDs are
negatively regulated by allosteric binding of dTTP, while DcdV is instead regulated by DifV. For a litany of reasons
based on preliminary studies described in the proposal, we hypothesize that activation of DcdV via inhibition of
DifV skews the cellular nucleotide pool. More specifically, DcdV drives an increase in dUTP concentration and
decrease in dCTP and dTTP concentrations as a two-fold phage defense mechanism, i.e., preventing
accumulation of dNTP substrates for phage genome replication and promoting dUMP incorporation into phage
genomes. Exactly how DcdV functions mechanistically, how this function is inhibited by DifV, and the contribution
of this system to bacterial survival, for example, as part of a phage defense mechanism remains to be elucidated.
We propose to study the mechanistic basis of DcdV function, its regulation by DifV, and the biological contribution
of this newly discovered regulatory system to bacterial physiology in V. cholerae and other bacteria. These aims
will be pursued at the cellular and atomic level using the tools of cell biology, genetics, biochemistry, microscopy,
and structural biology. By defining the mechanism and function of this novel CDA regulatory system we expect
that our research will have a broad impact in multiple disciplines across both prokaryotic and eukaryotic fields.
项目摘要:由El Tor Biotype引起的弧形霍乱的当前和第七大流行编码两个
新型的遗传岛称为颤音第七大流行岛1和2(VSP-1和VSP-2)。虽然
提议获得这些岛屿的收购是第七大流行的关键,这些基因的功能
几乎是未知的。该提案的总体目的是了解功能和法规
我们发现的新型细菌胞丁脱氨酶(CDA)调节系统已编码在VSP-1上
在许多其他蛋白质中。这个新的CDA调节系统由多域蛋白组成
命名为DCDV(脱氧胞苷脱氨酶颤音)及其抑制剂difv(DCDV抑制因子颤音)
在DCDV的222 NT区域中编码。这些基因首先被鉴定为我们的生物信息学分析
它们在细菌基因组中与VSP-1编码的DNCV/CAPV环状GMP-AMP噬菌体中显着cooccur
我们以前发现的国防系统。与DCDV-DIFV的潜在作用一致,以调节噬菌体
防御,在没有差异的情况下表达DCDV会导致V。
霍乱和大肠杆菌。脱氧胞苷脱氨酶(DCD)酶在维持维持方面起关键作用
细菌和真核生物中的核苷酸稳态,超突变和病毒防御
尊重,DCDV及其直系同源物与任何其他先前研究的DCD都大不相同。例如,全部
先前描述的DCD是单域蛋白,而DCDV具有相关的N末端核苷酸
激酶(NK)领域,我们的遗传研究表明对于DCDV活性至关重要。此外,其他DCD是
由DTTP的变构结合负调节,而DCDV则由DIFV调节。出于许多原因
基于提案中描述的初步研究,我们假设通过抑制DCDV的激活
差异偏向细胞核苷酸池。更具体地说,DCDV推动了DUTP浓度的增加,并且
DCTP和DTTP浓度降低,作为两倍的噬菌体防御机制,即防止
DNTP基材的积累用于噬菌体基因组复制,并将垃圾业推广到噬菌体
基因组。 DCDV的机械功能如何,该功能如何被DIFV抑制和贡献
例如,作为噬菌体防御机制的一部分,该系统对细菌的存活率仍有待阐明。
我们建议研究DCDV函数的机理基础,其对DIFV的调节和生物学贡献
在这种新发现的霍乱和其他细菌中细菌生理学的调节系统中。这些目标
将使用细胞生物学,遗传学,生物化学,显微镜,
和结构生物学。通过定义这种新型CDA调节系统的机制和功能,我们期望
我们的研究将对原核生物和真核领域的多个学科产生广泛的影响。
项目成果
期刊论文数量(0)
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Matthew B Neiditch其他文献
Matthew B Neiditch的其他文献
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{{ truncateString('Matthew B Neiditch', 18)}}的其他基金
The contribution of novel cytidine deaminase regulatory systems to bacterial evolution
新型胞苷脱氨酶调节系统对细菌进化的贡献
- 批准号:
10553666 - 财政年份:2021
- 资助金额:
$ 57.87万 - 项目类别:
The contribution of novel cytidine deaminase regulatory systems to bacterial evolution
新型胞苷脱氨酶调节系统对细菌进化的贡献
- 批准号:
10179834 - 财政年份:2021
- 资助金额:
$ 57.87万 - 项目类别:
X-ray Crystallographic Analysis of Diguanylate Cyclase Enzyme-Inhibitor Complexes
二鸟苷酸环化酶抑制剂复合物的 X 射线晶体分析
- 批准号:
8582834 - 财政年份:2013
- 资助金额:
$ 57.87万 - 项目类别:
X-ray Crystallographic Analysis of Diguanylate Cyclase Enzyme-Inhibitor Complexes
二鸟苷酸环化酶抑制剂复合物的 X 射线晶体分析
- 批准号:
8712661 - 财政年份:2013
- 资助金额:
$ 57.87万 - 项目类别:
Structural Biology of Multifunctional Bacterial Phosphatases
多功能细菌磷酸酶的结构生物学
- 批准号:
7631902 - 财政年份:2009
- 资助金额:
$ 57.87万 - 项目类别:
Structural Biology of Multifunctional Bacterial Phosphatases
多功能细菌磷酸酶的结构生物学
- 批准号:
8711660 - 财政年份:2009
- 资助金额:
$ 57.87万 - 项目类别:
Structural Biology of Multifunctional Bacterial Phosphatases
多功能细菌磷酸酶的结构生物学
- 批准号:
8117171 - 财政年份:2009
- 资助金额:
$ 57.87万 - 项目类别:
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