Polyphosphate - A Novel Member of the Proteostasis Network

多磷酸盐 - 蛋白质稳态网络的新成员

基本信息

批准号：
9118242
负责人：
Ursula H. Jakob
金额：
$ 45.65万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118242
关键词：
Affect Affinity Alzheimer&apos s Disease Amyloid Amyloid Fibrils Amyloid fibers Amyloidosis Back Bacteria Bacterial Infections Binding Biochemical Biological Process Blood coagulation Cells Client Development Disease Eukaryota Fiber Genetic Goals Health In Vitro Infection Intervention Knowledge Length Link Malignant Neoplasms Mediating Metals Microbial Biofilms Modeling Molecular Chaperones Molecular Conformation Names Nature Organism Pathogenesis Pathology Pharmacologic Substance Physiological Play Polymers Polyphosphates Polyps Process Prokaryotic Cells Property Protein-Folding Disease Proteins Research Resistance Resolution Role Stress Stress-Induced Protein Structure Time Toxic effect Work age related amyloid fibril formation amyloid formation antimicrobial base beta pleated sheet combat forgetting in vivo inorganic phosphate macromolecule member microbial monomer novel novel strategies pathogen polyanion prebiotics prevent protein aggregation protein folding protein function research study scaffold signal processing stoichiometry stress tolerance tool

项目摘要

DESCRIPTION (provided by applicant): Absolutely conserved, highly abundant, and present in all cells and organisms studied, polyphosphates (polyPs) are one of the most ancient macromolecules found on earth. They consist of long chains of phosphates, linked by high-energy phosphoanhydride bonds. PolyP has been shown to play crucial roles in bacterial pathogenesis, biofilm formation, stress resistance and blood clotting, and has been implicated in signaling processes and cancer. Despite these important functions, however, little is known about the mechanism(s) by which polyP influences these diverse processes. Based on our most recent discoveries we now postulate that polyP affects this wide and seemingly unrelated range of biological functions by using a single, unifying mechanism: serving as a scaffold that stabilizes protein folding intermediates. This would explain how polyP confers resistance to stress conditions that cause protein unfolding and accelerates processes, such as biofilm formation, which involve the stabilization of amyloid-like proteins in a fiber-forming conformation We propose to investigate the precise mechanism by which polyP influences these processes using a combination of genetic, biochemical, and structural approaches. We will exploit the facts that polyP- deficient bacteria are exquisitely sensitive towards the physiological antimicrobial HOCl (i.e., bleach) and impaired in biofilm formation to develop novel antimicrobials. We will investigate the role of polyP as member of the eukaryotic proteostasis network and expand on our discovery that polyP accelerates disease-related amyloid fiber formation, the leading cause of protein folding diseases, such as Alzheimer's Disease. These studies will reveal polyP's physiological role in eukaryotic organisms, significantly expanding the knowledge about this prebiotic molecule. The results will aid in the development of more effective antimicrobials and strategies to modulate the onset of age-related pathologies.

描述（由申请人提供）：聚磷酸盐 (polyPs) 绝对保守、高度丰富，存在于所有研究的细胞和生物体中，是地球上发现的最古老的大分子之一，它们由通过高能连接的长磷酸盐链组成。磷酸酐键已被证明在细菌发病机制、生物膜形成、应激抵抗和血液凝固中发挥着至关重要的作用，并且与信号传导过程和癌症有关。然而，人们对polyP影响这些不同过程的机制知之甚少，根据我们最近的发现，我们现在假设polyP通过使用单一的、统一的机制来影响这一广泛且看似不相关的生物功能。稳定蛋白质折叠中间体的支架这将解释polyP如何赋予对导致蛋白质展开的应激条件的抵抗力并加速生物膜形成等过程，这涉及淀粉样蛋白在纤维形成构象中的稳定。我们将结合遗传、生物化学和结构方法来研究多聚磷影响这些过程的精确机制，我们将利用多聚磷缺陷细菌对生理抗菌次氯酸（即漂白剂）极其敏感并且生物膜受损的事实。我们将研究polyP作为真核蛋白质稳态网络成员的作用，并扩展我们的发现，即polyP加速与疾病相关的淀粉样纤维形成，这是导致疾病的主要原因。这些研究将揭示多聚蛋白在真核生物中的生理作用，显着扩展对这种益生元分子的认识，这些结果将有助于开发更有效的抗菌药物和调节与年龄相关的发病的策略。病理学。