Mechanism and structural basis of amyloid fibril formation by serum amyloid A

描述（由申请人提供）：血清淀粉样蛋白A（SAA）属于高度保守的小蛋白家族，似乎在胆固醇代谢和炎症反应中发挥核心作用。SAA主要由肝脏合成并分泌到血浆中，在血浆中它与高密度脂蛋白（HDL）结合，但它也在正常和患病组织中表达，包括动脉粥样硬化斑块和阿尔茨海默病患者的大脑。在慢性炎症期间，SAA的浓度可增加高达1000倍，有时在主要器官中形成淀粉样原纤维沉积，导致通常致命的淀粉样蛋白A（AA）淀粉样变性疾病。AA淀粉样变性是目前世界上最常见的系统性淀粉样疾病之一，目前尚无治愈方法。在小鼠中，AA淀粉样变性可通过引起炎症反应来诱导。然而，一种特定的小鼠品系（CE/J）含有SAA的单一同种型（SAA 2.2），其在慢性炎症期间对体内淀粉样蛋白沉积具有抗性，尽管与淀粉样蛋白生成性SAA 1.1同种型具有94%的同一性。本研究的目的是研究小鼠同种型SAA 2.2和高度淀粉样蛋白生成的小鼠同种型SAA 1.1的淀粉样蛋白形成机制，以了解它们形成淀粉样蛋白的不同倾向的结构、生化和生物物理基础。使用各种分析、生物物理和生物化学方法，本申请的目的是研究（目的1）SAA 2.2和SAA 1.1淀粉样蛋白形成的机制，（目的2）锌、钙和HDL对SAA 2.2和SAA 1.1的结构、稳定性和淀粉样蛋白形成的作用，以及（目的3）SAA 1.1体内高淀粉样蛋白形成的结构基础。长期目标是了解SAA的结构、配体结合特性和淀粉样变性的分子基础，以设计有效的预防或治疗AA淀粉样变性的方法。考虑到SAA在正常和患病组织中的广泛表达谱及其大量推定功能，看起来SAA可能不仅仅是炎症的标志物，而是可能在许多炎症相关疾病的过程中发挥积极作用。因此，更好地了解SAA的生物化学和生物物理特性，正如所提出的研究所产生的那样，可能有助于了解它如何参与炎症过程。

DESCRIPTION (provided by applicant): Serum amyloid A (SAA) belongs to a highly conserved family of small proteins that appear to play a central role in cholesterol metabolism and the inflammatory response. SAA is mainly synthesized by the liver and secreted to the plasma where it binds to high density lipoprotein (HDL), but it is also expressed in normal and diseased tissue, including atherosclerotic plaques and the brains of patients with Alzheimer's disease. During chronic inflammation the concentration of SAA can increase up to 1000 fold, and sometimes form amyloid fibril deposits in major organs, leading to the usually fatal disease of amyloid A (AA) amyloidosis. There is no cure for AA amyloidosis, which is currently one of the most common systemic amyloid diseases worldwide. In mouse, AA amyloidosis can be induced by causing an inflammatory response. Nevertheless, a particular mouse strain (CE/J) contains a single isoform of SAA (SAA2.2) that is resistant to amyloid deposition in vivo during chronic inflammation, despite being 94% identical to the amyloidogenic SAA1.1 isoform. The goal of the proposed research is to study the amyloid formation mechanism of the mouse isoform SAA2.2 and the highly amyloidogenic mouse isoform SAA1.1 to understand the structural, biochemical, and biophysical basis for their different propensities for amyloid formation. Using various, analytical, biophysical, and biochemical methods, the aims of this application are to investigate (Aim 1) the mechanism of SAA2.2 and SAA1.1 amyloid formation, (Aim 2) the role of zinc, calcium, and HDL on the structure, stability and amyloid formation of SAA2.2 and SAA1.1, and (Aim 3) the structural basis for the high in vivo amyloidogenicity of SAA1.1. The long-term goal is to understand the structure, ligand-binding properties, and the molecular basis for the amyloidogenicity of SAA to allow the design of effective preventive or therapeutic approaches against AA amyloidosis. Considering the wide expression profile of SAA in normal and diseased tissue, and its large number of putative functions, it appears that SAA may not just be a marker for inflammation, but rather, may play an active role in the process of many inflammation- related diseases. Therefore, a better understanding of the biochemical and biophysical properties of SAA, as will result from the proposed studies, may shed some light towards understanding how it participates in the process of inflammation.