Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK.
Molecules. 2022 Feb 15;27(4):1293. doi: 10.3390/molecules27041293.
A wide variety of oligomeric structures are formed during the aggregation of proteins associated with neurodegenerative diseases. Such soluble oligomers are believed to be key toxic species in the related disorders; therefore, identification of the structural determinants of toxicity is of upmost importance. Here, we analysed toxic oligomers of α-synuclein and its pathological variants in order to identify structural features that could be related to toxicity and found a novel structural polymorphism within G51D oligomers. These G51D oligomers can adopt a variety of β-sheet-rich structures with differing degrees of α-helical content, and the helical structural content of these oligomers correlates with the level of induced cellular dysfunction in SH-SY5Y cells. This structure-function relationship observed in α-synuclein oligomers thus presents the α-helical structure as another potential structural determinant that may be linked with cellular toxicity in amyloid-related proteins.
在与神经退行性疾病相关的蛋白质聚集过程中，会形成多种寡聚体结构。这类可溶性寡聚体被认为是相关疾病中的关键毒性物质；因此，确定毒性的结构决定因素至关重要。在这里，我们分析了α-突触核蛋白及其病理变体的毒性寡聚体，以鉴定可能与毒性相关的结构特征，结果在 G51D 寡聚体中发现了一种新的结构多态性。这些 G51D 寡聚体可以采用多种富含β-折叠的结构，具有不同程度的α-螺旋含量，并且这些寡聚体的螺旋结构含量与在 SH-SY5Y 细胞中诱导的细胞功能障碍水平相关。因此，在α-突触核蛋白寡聚体中观察到的这种结构-功能关系表明，α-螺旋结构是另一个可能与淀粉样相关蛋白的细胞毒性相关的潜在结构决定因素。
