Polyphosphate - A Novel Member of the Proteostasis Network

 描述(申请人提供)：绝对保守，高度丰富，存在于所有被研究的细胞和生物体中，聚磷酸盐(息肉)是地球上发现的最古老的大分子之一。它们由长链的磷酸盐组成，通过高能的磷酸酸酐键连接起来。息肉已被证明在细菌发病、生物被膜形成、应激抵抗和血液凝结中发挥关键作用，并与信号转导和癌症有关。然而，尽管有这些重要的功能，人们对息肉影响这些不同过程的机制(S)知之甚少。根据我们最新的发现，我们现在假设，息肉通过使用一个单一的、统一的机制来影响这一广泛且看似无关的生物功能：作为稳定蛋白质折叠中间体的支架。这将解释息肉如何对导致蛋白质展开和加速生物膜形成等过程的应激条件产生抵抗力，这些过程涉及淀粉样蛋白在纤维形成构象中的稳定。我们建议结合遗传、生化和结构方法来研究息肉影响这些过程的精确机制。我们将利用息肉缺陷细菌对生理抗菌剂HOCl(即漂白剂)极其敏感的事实，并在生物被膜形成过程中受到损害，以开发新的抗菌剂。我们将调查息肉作为真核蛋白平衡网络成员的作用，并扩展我们的发现，即息肉加速疾病相关淀粉样纤维的形成，这是蛋白质折叠疾病(如阿尔茨海默病)的主要原因。这些研究将揭示息肉在真核生物中的生理作用，显著扩大对这种益生菌分子的了解。这些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的发生。

 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.