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首次相互作用，因此粘附素介导的结合是分化、定植、生物膜形成和病原体入侵的前奏。这些事件进而导致发病率和死亡率的并发症，尤其常见于免疫功能低下和慢性病患者。白色念珠菌 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同聚集以介导多种微生物感染。 Als 粘附素对于组织和留置装置上持久且耐药的生物膜的形成也很重要。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。该提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一个特征，这些序列增强粘附、真菌聚集和宿主入侵。这一假设基于我们的发现，即 Als5p 导致与淀粉样蛋白样特征的粘附，纯化的 Als5p 可以形成真正的淀粉样蛋白，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于 Als 介导的细胞聚集至关重要的工作假设。 (2) 我们将检验这样的假设：Als 蛋白中的这些淀粉样蛋白形成序列对于 Als 启动的生物膜形成至关重要。 (3)在Als蛋白中，糖基化串联重复序列遵循淀粉样蛋白形成序列，这些重复序列大大增加了粘附活性。因此，我们将检验这样的假设：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。这项工作的创新之处在于它结合了两个重要概念：淀粉样蛋白相互作用和导致生物膜形成的病原体粘附。我们也是第一个研究致病性和其他真菌粘附素中富含苏氨酸的重复序列的结构和功能的小组。这些目标的完成将为生物膜形成的初始事件提供更好的模型，并将发现淀粉样蛋白形成序列是否对于真菌中生物膜的粘附至关重要。如果这一假设得到支持，结果将在抗生物膜和抗淀粉样蛋白治疗药物的搜索之间建立联系。

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.