MEK1 transduces the prion protein N2 fragment antioxidant effects
MEK1 transduces the prion protein N2 fragment antioxidant effects
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DOI：
10.1007/s00018-014-1777-y
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发表时间：
2015-04-01
影响因子：
8
通讯作者：
Collins, S. J.
中科院分区：
文献类型：
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作者：
Haigh, C. L.;McGlade, A. R.;Collins, S. J.
朊病毒蛋白（PrPC）错误折叠时与一组称为传染性海绵状脑病或朊病毒疾病的致命神经退行性疾病有因果关系。PrPC的正常功能仍不完全确定，这些研究因PrPC翻译后修饰（如内部切割）而复杂化，这可能改变、激活或灭活该蛋白的功能。氧化应激诱导β-裂解，并且该裂解事件的N-末端产物N2证明了针对氧化应激的细胞保护性应答。在体外细胞模型中研究了N2介导细胞抗氧化保护的机制。N2保护由铜结合到octrepeat结构域来调节，指导内化的途径，从而刺激MEK 1信号传导。精确的膜相互作用的N2，由铜饱和度，并涉及铜协调octrepeat区域和结构赋予的N-末端的多元区域的脯氨酸基序，是必不可少的正确参与这一途径。PrPC翻译后修饰的现象，如切割和铜配位，作为激活或失活某些功能的分子“开关”，提供了新的见解明显的多功能性的PrPC。
The prion protein (PrPC) when mis-folded is causally linked with a group of fatal neurodegenerative diseases called transmissible spongiform encephalopathies or prion diseases. PrPC normal function is still incompletely defined with such investigations complicated by PrPC post-translational modifications, such as internal cleavage, which feasibly could change, activate, or deactivate the function of this protein. Oxidative stress induces beta-cleavage and the N-terminal product of this cleavage event, N2, demonstrates a cellular protective response against oxidative stress. The mechanisms by which N2 mediates cellular antioxidant protection were investigated within an in vitro cell model. N2 protection was regulated by copper binding to the octarepeat domain, directing the route of internalisation, which stimulated MEK1 signalling. Precise membrane interactions of N2, determined by copper saturation, and involving both the copper-co-ordinating octarepeat region and the structure conferred upon the N-terminal polybasic region by the proline motif, were essential for the correct engagement of this pathway. The phenomenon of PrPC post-translational modification, such as cleavage and copper co-ordination, as a molecular "switch" for activation or deactivation of certain functions provides new insight into the apparent multi-functionality of PrPC.