Prion protein interaction with the C-terminal SH3 domain of Grb2 studied using NMR and optical spectroscopy
Prion protein interaction with the C-terminal SH3 domain of Grb2 studied using NMR and optical spectroscopy
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DOI：
10.1021/bi0494828
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发表时间：
2004-08-17
期刊：
影响因子：
2.9
通讯作者：
Wüthrich, K
中科院分区：
文献类型：
--
作者：
Lysek, DA;Wüthrich, K
传染性海绵状脑病仅在表达宿主编码的朊病毒蛋白（PrP）的生物体中观察到。在健康生物体中发现的PrP细胞亚型的功能迄今尚未确定，尽管有迹象表明在神经元中的信号转导中起作用。为了进一步了解细胞PrP的功能特性，本文研究了鼠生长因子受体结合蛋白2（Grb 2）的C-末端SH 3结构域与鼠PrP的结合，使用NMR，荧光和圆二色光谱。因此，发现鼠PrP中的SH 3结合位点在残基100-109的高度保守区域中，其在位置101和104中含有脯氨酸。当这两种脯氨酸中的任何一种被亮氨酸取代时，K-D值为5.5 μ M的蛋白质-蛋白质相互作用被消除。在人类中，在Gerstmann-Straussler-Scheinker综合征患者中发现了两种相应的Pro -> Leu交换。因此，本研究的结果表明，氨基酸交换可能会影响一个复杂的信号转导级联中的特定蛋白质-蛋白质相互作用的可能机制，这可能是健康和疾病的功能意义。
Transmissible spongiform encephalopathies have been observed exclusively in organisms expressing the host-encoded prion protein (PrP). The function of the cellular isoform of PrP found in healthy organisms has so far not been identified, although there are indications of a role in signal transduction in neurons. To gain further insight into the functional properties of cellular PrP, this paper investigated the binding of the C-terminal SH3 domain of the murine growth factor receptor-bound protein 2 (Grb2) to the murine PrP, using NMR, fluorescence, and circular dichroism spectroscopy. The SH3-binding site in murine PrP was thus found to be in the highly conserved region of residues 100-109, which contains prolines in positions 101 and 104. The protein-protein interaction, with a K-D value of 5.5 muM, is abolished when either of these two prolines is replaced by leucine. In humans, two corresponding Pro --> Leu exchanges are found in patients who present with the Gerstmann-Straussler-Scheinker syndrome. The results of the present study thus indicate a possible mechanism by which amino acid exchanges could influence a specific protein-protein interaction in a complex signal transduction cascade, which might be of functional significance in health and disease.