Polyphosphate - A Novel Member of the Proteostasis Network

 描述（由申请人提供）：多聚磷酸盐（polyPs）是地球上发现的最古老的大分子之一，绝对保守，高度丰富，存在于所有研究的细胞和生物体中。它们由长链的磷酸盐组成，通过高能磷酸酐键连接。PolyP已被证明在细菌发病机制，生物膜形成，抗应激和血液凝固中起着至关重要的作用，并与信号传导过程和癌症有关。然而，尽管有这些重要的功能，人们对polyP影响这些不同过程的机制知之甚少。基于我们最近的发现，我们现在假设polyP通过使用单一的统一机制影响这一广泛且看似无关的生物功能范围：作为稳定蛋白质折叠中间体的支架。这将解释聚P如何赋予抵抗压力条件，导致蛋白质展开和加速过程，如生物膜的形成，这涉及稳定的淀粉样蛋白在纤维形成的构象我们建议调查的精确机制，聚P影响这些过程使用遗传，生物化学和结构的方法相结合。我们将利用聚P缺陷型细菌对生理抗微生物剂HOCl极其敏感的事实（即，漂白剂）和生物膜形成受损以开发新的抗微生物剂。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加速疾病相关的淀粉样纤维形成，这是蛋白质折叠疾病的主要原因，如阿尔茨海默病。这些研究将揭示polyP在真核生物中的生理作用，大大扩展了关于这种益生元分子的知识。研究结果将有助于开发更有效的抗菌剂和策略，以调节与年龄相关的病理学的发病。

 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.