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Amyloid-like Interactions in Yeast Cell Adhesion

酵母细胞粘附中的淀粉样蛋白样相互作用

基本信息

批准号：
8069127
负责人：
PETER N LIPKE
金额：
$ 34.97万
依托单位：
BROOKLYN COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-20 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069127
关键词：
Adherence Adhesions Amino Acid Sequence Amyloid Bacterial Adhesins Binding Binding Sites Bioinformatics Candida Candida albicans Cell Adhesion Cell Adhesion Molecules Cell Aggregation Cell Wall Cell surface Chronic Disease Collaborations Complex Databases Drug resistance Event Experimental Models Fungal Genome Genes Goals Immunocompromised Host Immunoglobulin Domain Individual Infection Lead Life Cycle Stages Ligand Binding Ligands Mediating Medical Microbial Biofilms Modeling Molecular Morbidity - disease rate Mutate Open Reading Frames Outcome Pathogenesis Pathway interactions Patients Pattern Peptide Sequence Determination Peptides Preventive Intervention Property Proteins Qualifying Reagent Recording of previous events Research Role Saccharomyces cerevisiae Site Structure Surface System Tandem Repeat Sequences Tertiary Protein Structure Testing Therapeutic Agents Therapeutic Intervention Tissues Work Yeasts amyloid formation base candidemia chemical property crosslink fungus glycosylation implantable device innovation knowledge base microbial mortality mutant pathogen protein aminoacid sequence synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): Cell surface adhesins mediate the first interactions of fungi with mammalian hosts, so adhesin-mediated binding is a prelude to differentiation, colonization, biofilm formation and pathogenic invasion. These events in turn lead to complications of morbidity and mortality, especially common in immunocompromised and chronic disease patients. The C. albicans Als adhesins are implicated in pathogenesis and biofilm formation. They bind to mammalian tissues, cause fungal cell aggregation, and also co-aggregate with other microbial pathogens to mediate polymicrobial infections. Als adhesins are also important in formation of persistent and drug-resistant biofilms in tissues and on indwelling devices. Our long-term goal is to understand the roles for cell adhesion proteins in fungal life cycles and pathogenesis. The central hypothesis of this proposal is that amyloid-forming sequences are a feature of biofilm-forming adhesins, and these sequences potentiate adhesion, fungal aggregation and host invasion. This hypothesis is based on our findings that Als5p causes adherence with amyloid-like features, that the purified Als5p can form authentic amyloids, and that bioinformatic analyses reveal amyloid-forming sequences in many biofilm-associated microbial adhesins. Three specific aims will test the amyloid/ biofilm hypothesis: (1) To determine the role of specific sequences in amyloid formation and microbial adherence, we will test the working hypothesis that the amyloid-forming sequences are essential for Als-mediated cellular aggregation. (2) We will test the hypothesis that these amyloid-forming sequences in Als proteins are essential for Als-initiated biofilm formation. (3) In Als proteins, glycosylated tandem repeats follow the amyloid-forming sequences, and these repeats greatly increase adhesion activity. We will therefore test the hypothesis that the peptide sequences and glycosylation patterns in the Als repeats modulate amyloid formation to promote cellular aggregation and biofilm formation. The proposed work is innovative in its conjunction of two important concepts: amyloid-like protein interactions and adherence of pathogens leading to biofilm formation. We are also the first group to work on structure and function of Thr-rich repeat sequences in pathogenic and other fungal adhesins. Completion of these aims will lead to better defined models for the initial events in biofilm formation, and will discover whether amyloid-forming sequences are essential for biofilm adherence in fungi. If the hypothesis is supported, the results will establish connections between searches for anti-biofilm and anti-amyloid therapeutic agents.

描述（由申请人提供）：细胞表面粘附素介导真菌与哺乳动物宿主的第一次相互作用，因此粘附素介导的结合是分化、定殖、生物膜形成和病原体入侵的前奏。这些事件反过来导致并发症的发病率和死亡率，特别是常见于免疫功能低下和慢性疾病患者。梭白念珠菌Als粘附素与发病机制和生物膜形成有关。它们与哺乳动物组织结合，引起真菌细胞聚集，并且还与其他微生物病原体共聚集以介导多种微生物感染。Als粘附素在组织中和留置装置上的持久性和耐药性生物膜的形成中也是重要的。我们的长期目标是了解细胞粘附蛋白在真菌生命周期和发病机制中的作用。该建议的中心假设是淀粉样蛋白形成序列是生物膜形成粘附素的特征，并且这些序列增强粘附、真菌聚集和宿主入侵。这一假设是基于我们的发现，即Als 5 p导致淀粉样特征的粘附，纯化的Als 5 p可以形成真实的淀粉样蛋白，并且生物信息学分析揭示了许多生物膜相关微生物粘附素中的淀粉样蛋白形成序列。三个具体目标将测试淀粉样蛋白/生物膜假说：（1）为了确定特定序列在淀粉样蛋白形成和微生物粘附中的作用，我们将测试淀粉样蛋白形成序列对Als介导的细胞聚集至关重要的工作假说。(2)我们将测试的假设，这些淀粉样蛋白形成序列的Als蛋白是必不可少的Als启动的生物膜形成。(3)在Als蛋白中，糖基化的串联重复序列跟随淀粉样蛋白形成序列，并且这些重复序列极大地增加粘附活性。因此，我们将测试这样的假设，即Als重复序列中的肽序列和糖基化模式调节淀粉样蛋白形成以促进细胞聚集和生物膜形成。拟议的工作是创新的两个重要概念的结合：淀粉样蛋白的相互作用和病原体的粘附导致生物膜的形成。我们也是第一个研究病原体和其他真菌粘附素中富含Th重复序列的结构和功能的小组。这些目标的完成将导致更好地定义模型的初始事件在生物膜形成，并将发现淀粉样蛋白形成序列是否是必不可少的真菌生物膜粘附。如果这一假设得到支持，结果将建立抗生物膜和抗淀粉样蛋白治疗剂之间的联系。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Does Candida albicans Als5p Amyloid Play a Role in Commensalism in Caenorhabditis elegans?

DOI：
10.1128/ec.00020-13
发表时间：
2013-05-01
期刊：
EUKARYOTIC CELL
影响因子：
0
作者：
Bois, Michael;Singh, Sean;Garcia, Melissa C.
通讯作者：
Garcia, Melissa C.

Strengthening relationships: amyloids create adhesion nanodomains in yeasts.

DOI：
10.1016/j.tim.2011.10.002
发表时间：
2012-02
期刊：
TRENDS IN MICROBIOLOGY
影响因子：
15.9
作者：
Lipke, Peter N.;Garcia, Melissa C.;Alsteens, David;Ramsook, Caleen B.;Klotz, Stephen A.;Dufrene, Yves F.
通讯作者：
Dufrene, Yves F.

Single-molecule imaging and functional analysis of Als adhesins and mannans during Candida albicans morphogenesis.

DOI：
10.1021/nn304505s
发表时间：
2012-12-21
期刊：
ACS NANO
影响因子：
17.1
作者：
Beaussart, Audrey;Alsteens, David;El-Kirat-Chatel, Sofiane;Lipke, Peter N.;Kucharikova, Sona;Van Dijck, Patrick;Dufrene, Yves F.
通讯作者：
Dufrene, Yves F.

On the evolution of fungal and yeast cell walls.

DOI：
10.1002/yea.1787
发表时间：
2010-08
期刊：
YEAST
影响因子：
2.6
作者：
Xie, Xianfa;Lipke, Peter N.
通讯作者：
Lipke, Peter N.

Between Amyloids and Aggregation Lies a Connection with Strength and Adhesion.

淀粉样蛋白和聚集之间存在着强度和粘附力的联系。

DOI：
10.1155/2014/815102
发表时间：
2014
期刊：
New journal of science
影响因子：
0
作者：
Lipke,PeterN;Ramsook,Caleen;Garcia-Sherman,MelissaC;Jackson,DesmondN;Chan,ChoXJ;Bois,Michael;Klotz,StephenA
通讯作者：
Klotz,StephenA