Cellular Mechanisms and Consequences of Protein Misfolding and Resolution

 描述(由申请人提供)：纯蛋白质或普里恩假说假设，细胞生理学的变化源于宿主编码的蛋白质(普里恩)重新折叠为改变其正常功能的替代构象。这一过程中的一个中心事件是 将这些替代构象组装成有序的淀粉样聚集体，它与相同蛋白质的其他构象的折叠结合，从而形成模板。然而，淀粉样蛋白的积累不能很好地预测细胞表型的变化，我们最近的研究表明，Pron，更广泛地说，淀粉样蛋白，生物学可能来自于由多个以前没有预料到的和目前了解较少的系统限制的交叉点创建的独特的稳态生态位。目前的知识差距是该领域取得进展的关键障碍，因为我们无法解释、预测并因此利用体内Pron错误折叠和其表型效应之间的联系。我们的长期目标是通过发展一种基于系统的理解来弥合这一差距，该理解融合了蛋白质质量控制途径、蛋白质序列和构象以及细胞生物学。为此，我们正在利用Prion生物学的神秘方面，包括序列变异、显性负抑制、细胞骨架相互作用、菌株显性和Prion相互作用，来揭示定义系统中平衡的贡献者和机制，创建与每个构象状态兼容的不同的自我平衡生态位，并诱导沿着这些连续体的转变。

 DESCRIPTION (provided by applicant): The protein-only or prion hypothesis posits that changes in cellular physiology arise from the refolding of host- encoded proteins (prions) to alternative conformations that alter their normal functions. A central event in this process is the assembly of these alternative conformers into ordered amyloid aggregates, which associate with, incorporate, and thereby template the refolding other conformers of the same protein. However, the accumulation of amyloid is a poor predictor of changes in cellular phenotype, and our recent studies reveal that prion, and more generally amyloid, biology likely arises from unique homeostatic niches created by an intersection of multiple, previously unanticipated, and currently poorly understood constraints of the system. This current gap in knowledge is a critical barrier to progress in the field because we are unable to explain, predict and therefore exploit the link between prion misfolding and its phenotypic effects in vivo. Our long-term goal is to bridge this gap by developing a system-based understanding of prion biology that integrates protein quality control pathways, prion protein sequence and conformation, and cell biology. Toward this end, we are exploiting enigmatic aspects of prion biology including sequence variants, dominant negative inhibition, cytoskeletal interactions, strain dominance and prion interactions to reveal the contributors and mechanisms that define balance in the system, create distinct homeostatic niches compatible with each conformational state, and induce transitions along these continuums.