Role of C-terminal truncations of SAA protein for fibril formation and seeding in AA amyloidosis

SAA 蛋白 C 端截短对 AA 淀粉样变性中原纤维形成和播种的作用

• 批准号: 254967848
• 负责人: Dr. Christian Haupt
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/254967848?language=en
• 关键词: Role; terminal; truncations; SAA; protein

Systemic AA amyloidosis is a conformational disease that affects both animals and humans and that is caused by AA amyloid fibrils. These filaments consist of N-terminal fragments of serum amyloid A (SAA) protein, but different clinical variants of the disease are associated with different SAA protein fragments. These data suggest an involvement of different fibril strains in different disease manifestations. To test these ideas, I will here probe the relationship between C-terminal truncation, proteolysis and fibril formation, and dissect out the structural effects of C-terminal truncation on protein structure and fibrillogenesis. Obtained results will then be used to explore whether or how seeding might vary in efficiency with fibril structure or sequence complementarity (species barrier) and whether certain fibril morphologies are able to propagate structural specifics or phenotypic manifestations in a strain-type fashion. Proposed experiments range from protein biochemical techniques and biophysics to cell biological and animal studies in mice. Expected results data will provide vital information for understanding the nature and molecular etiology of AA amyloidosis and the effectiveness of common molecular mechanisms in different types of conformational diseases.

系统性AA淀粉样变性是一种影响动物和人类的构象疾病，由AA淀粉样纤维引起。这些细丝由血清淀粉样蛋白A（SAA）蛋白的N-末端片段组成，但该疾病的不同临床变体与不同的SAA蛋白片段相关。这些数据表明不同的原纤维株参与不同的疾病表现。为了验证这些想法，我将在这里探测C-末端截短，蛋白水解和原纤维形成之间的关系，并剖析了C-末端截短对蛋白质结构和原纤维形成的结构影响。然后将使用获得的结果来探索接种是否或如何在效率上随原纤维结构或序列互补性（物种屏障）而变化，以及某些原纤维形态是否能够以菌株类型的方式传播结构特异性或表型表现。拟议的实验范围从蛋白质生物化学技术和生物物理学到细胞生物学和小鼠动物研究。预期结果数据将为了解AA淀粉样变性的性质和分子病因学以及不同类型构象疾病中常见分子机制的有效性提供重要信息。

项目成果

Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis

• DOI: 10.1073/pnas.1707120114
• 发表时间: 2017-08-08
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Jayaraman, Shobini;Gantz, Donald L.;Gursky, Olga
• 通讯作者: Gursky, Olga

Cellular mechanism of fibril formation from serum amyloid A1 protein

• DOI: 10.15252/embr.201643411
• 发表时间: 2017-08-01
• 期刊: EMBO REPORTS
• 影响因子: 7.7
• 作者: Claus, Stephanie;Meinhardt, Katrin;Faendrich, Marcus
• 通讯作者: Faendrich, Marcus