School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Center of Novel Biomaterials, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Laboratory of Drosophila Research, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Cell Chem Biol. 2021 Feb 18;28(2):180-190.e6. doi: 10.1016/j.chembiol.2020.12.010. Epub 2021 Jan 13.
The accumulation of α-synuclein amyloid fibrils in the brain is linked to Parkinson's disease and other synucleinopathies. The intermediate species in the early aggregation phase of α-synuclein are involved in the emergence of amyloid toxicity and considered to be the most neurotoxic. The N-terminal region flanking the non-amyloid-β component domain of α-synuclein has been implicated in modulating its aggregation. Herein, we report the development of a SUMO1-derived peptide inhibitor (SUMO1(15-55)), which targets two SUMO-interacting motifs (SIMs) within this aggregation-regulating region and suppresses α-synuclein aggregation. Molecular modeling, site-directed mutagenesis, and binding studies are used to elucidate the mode of interaction, namely, via the binding of either of the two SIM sequences on α-synuclein to a putative hydrophobic binding groove on SUMO1(15-55). Subsequent studies show that SUMO1(15-55) also reduces α-synuclein-induced cytotoxicity in cell-based and Drosophila disease models.
α-突触核蛋白淀粉样纤维在大脑中的积累与帕金森病和其他突触核蛋白病有关。α-突触核蛋白早期聚集阶段的中间产物参与了淀粉样毒性的出现，被认为是最具神经毒性的。α-突触核蛋白中非淀粉样β成分域侧翼的 N 端区域被认为可以调节其聚集。本文报道了一种 SUMO1 衍生肽抑制剂（SUMO1（15-55））的开发，该抑制剂针对该聚集调节区域内的两个 SUMO 相互作用基序（SIM），并抑制 α-突触核蛋白聚集。分子建模、定点突变和结合研究用于阐明相互作用模式，即通过将两个 SIM 序列中的任一个与 SUMO1（15-55）上的假定疏水性结合槽结合，从而与 α-突触核蛋白结合。随后的研究表明，SUMO1（15-55）还可以降低基于细胞和果蝇疾病模型中α-突触核蛋白诱导的细胞毒性。
