Biochemical and structural studies of amyloid enhancing factor

淀粉样蛋白增强因子的生化和结构研究

• 批准号: 260764931
• 负责人: Professor Dr. Marcus Fändrich
• 金额: --
• 依托单位: Institut für Proteinbiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/260764931?language=en
• 关键词: Biochemical; structural; studies; amyloid; enhancing

Systemic AA amyloidosis is a protein misfolding disease that affects humans, mammals and birds. The disease is caused by the formation and deposition of AA amyloid fibrils in spleen, kidneys and liver. While AA amyloid fibrils are composed of fragments of the serum amyloid A (SAA) 1.1 protein, there is long-standing evidence that injection of crude spleen extracts, termed amyloid enhancing factor (AEF), into appropriate recipients accelerates amyloid deposition. As these partially enriched spleen extracts were found to often comprise at least small levels of AA fibrils, a prion-like mechanism of propagation was suggested, although the active species was never fully purified. Using modern biochemical methods and a cell model of SAA fibril formation we will isolate AEF from its native source to analyze its molecular properties with a battery of biophysical methodologies. Resulting hypotheses concerning the constitutional and conformational composition can then the tested by in vitro reconstitution. As spreading is an important feature of conformational diseases in general, expected data could be of broad scientific and public interest.

全身性AA淀粉样变性是一种影响人类，哺乳动物和鸟类的蛋白质错误折叠疾病。该疾病是由脾脏，肾脏和肝脏中AA淀粉样蛋白原纤维的形成和沉积引起的。虽然AA淀粉样蛋白原纤维由血清淀粉样蛋白A（SAA）1.1蛋白的片段组成，但长期以来有证据表明，将粗脾脏提取物（称为淀粉样蛋白增强因子（AEF））注射到适当的受体中，并加速淀粉样蛋白的沉积。由于发现这些部分富集的脾脏提取物通常至少包含少量的AA原纤维，因此提出了一种类似prion的传播机制，尽管活性物种从未完全纯化。使用现代化的生化方法和SAA原纤维形成的细胞模型，我们将用天然来源分离AEF，以用一系列生物物理方法分析其分子特性。然后，关于宪法和构象成分的假设可以通过体外重构进行测试。由于扩散是构象疾病的重要特征，因此预期的数据可能具有广泛的科学和公共利益。

项目成果

Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits

• DOI: 10.1073/pnas.1523496113
• 发表时间: 2016-05-17
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Kollmer, Marius;Meinhardt, Katrin;Faendrich, Marcus
• 通讯作者: Faendrich, Marcus

Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids

• DOI: 10.1038/s41467-019-09033-z
• 发表时间: 2019-03-07
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Liberta, Falk;Loerch, Sarah;Schmidt, Matthias
• 通讯作者: Schmidt, Matthias