Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria.
Cell Rep. 2012 Aug 30;2(2):358-71. doi: 10.1016/j.celrep.2012.06.012. Epub 2012 Jul 26.
The inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SERF1a originates from its atypical ability to specifically distinguish between amyloid and nonamyloid aggregation. This inherently unstructured protein directly affected the aggregation kinetics of a broad range of amyloidogenic proteins in vitro, while being inactive against nonamyloid aggregation. A representative biophysical analysis of the SERF1a:α-synuclein (aSyn) complex revealed that the amyloid-promoting activity resulted from an early and transient interaction, which was sufficient to provoke a massive increase of soluble aSyn amyloid nucleation templates. Therefore, the autonomous amyloid-modifying activity of SERF1a observed in living organisms relies on a direct and dedicated manipulation of the early stages in the amyloid aggregation pathway.
错误折叠蛋白聚集体的固有细胞毒性对淀粉样变性疾病的发病机制有很大影响。最近表明，一类进化保守的蛋白质，称为 MOAG-4/SERF，通过一种自主但尚未解释的模式，极大地改变了淀粉样毒性。我们表明，人类 SERF1a 的生物学功能源于其独特的能力，能够特异性区分淀粉样和非淀粉样聚集。这种无规卷曲的蛋白质直接影响了广泛的淀粉样蛋白原性蛋白质在体外的聚集动力学，而对非淀粉样聚集没有活性。对 SERF1a：α-突触核蛋白（aSyn）复合物的代表性生物物理分析表明，淀粉样促进活性源于早期和短暂的相互作用，足以引发大量可溶性 aSyn 淀粉样核模板的形成。因此，在生物体中观察到的 SERF1a 的自主淀粉样修饰活性依赖于对淀粉样聚集途径早期阶段的直接和专门的操作。
