(II) 与α和β-synuclein的特定场所相互作用:弥合金属结合和聚合之间的分子间隙
Andrés Binolfi1, Gonzalo R Lamberto, Rosario Duran
1Instituto de Biología Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina.
Journal of the American Chemical Society
|August 13, 2008
概括
铜与α-synuclein (AS) 和β-synuclein (BS) 的结合发生在两个不同的N-终端位点,其中Met1至关重要. 这样可以澄清铜.
科学领域:
- 生物有机化学 生物有机化学
- 神经退行性疾病 神经退行性疾病
- 蛋白质的错误折叠 蛋白质的错误折叠
背景情况:
- 阿尔法-同核素 (AS) 聚合是帕金森病 (PD) 发病的核心.
- 蛋白与金属的相互作用,特别是与Cu (II) 的相互作用,涉及AS聚合和氧化损伤.
- 之前的工作确定了与AS结合的特定Cu (II),触发了与PD相关的聚合.
研究的目的:
- 阐明AS中的Cu(II) 结合特异性的结构细节.
- 描述β-同核素 (BS) 的金属结合特性,一种天然同类物.
- 了解特定残留物和结合点在Cu (II) -同核素相互作用中的作用.
主要方法:
- 设计局部定向和域截断的AS突变.
- 使用NMR,EPR,UV-vis,CD光谱学和MALDI MS.进行Cu(II) 复合物的表征.
- 对AS和BS的金属结合性能进行比较分析.
主要成果:
- 在AS和BS的N端确定了两个独立的,不相互作用的Cu (II) 结合位.
- 证实Met1是两个蛋白质中的主要Cu (II) 定残留物.
- 较高亲和度的Cu(II) 结合涉及Met1的N端氨基群;较低亲和度涉及His残留的伊米达环.
结论:
- Cu(II) 与突核素的结合发生在特定的N端位,具有亚微分子亲和力.
- 结合C端Cu (II) 是非特异性的,其亲和力非常低.
- 这些发现提升了对Cu (II) 在AS聚合中的作用和BS在PD中的抑制机制的理解.
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