Departamento de Química, Cinvestav, Av. IPN 2508, San Pedro Zacatenco, México, D.F., 07360, México.
J Phys Chem B. 2013 Jan 24;117(3):789-99. doi: 10.1021/jp310000h. Epub 2013 Jan 15.
The prion protein (PrP(C)) binds Cu(II) in its N-terminal region, and it is associated to a group of neurodegenerative diseases termed transmissible spongiform encephalopaties (TSEs). The isoform PrP(Sc), derived from the normal PrP(C), is the pathogenic agent of TSEs. Using spectroscopic techniques (UV-vis absorption, circular dichroism, and electron paramagnetic resonance) and electronic structure calculations, we obtained a structural description for the different pH-dependent binding modes of Cu(II) to the PrP(92-96) fragment. We have also evaluated the possibility of water molecule ligation to the His96-bound copper ion. Geometry-optimized structural models that reproduce the spectroscopic features of these complexes are presented. Two Cu(II) binding modes are relevant at physiological pH: 4N and 3NO equatorial coordination modes; these are best described by models with no participation of water molecules in the coordination sphere of the metal ion. In contrast, the 2N2O and N3O coordination modes that are formed at lower pH involve the coordination of an axial water molecule. This study underscores the importance of including explicit water molecules when modeling copper binding sites in PrP(C).
朊病毒蛋白（PrP(C)）在其 N 端区域结合 Cu(II)，并与一组称为传染性海绵状脑病（TSEs）的神经退行性疾病有关。源自正常 PrP(C)的同工型 PrP(Sc)是 TSEs 的致病因子。使用光谱技术（紫外可见吸收、圆二色性和电子顺磁共振）和电子结构计算，我们获得了不同 pH 值依赖性 Cu(II)与 PrP(92-96)片段结合模式的结构描述。我们还评估了水分子与 His96 结合铜离子配位的可能性。提出了再现这些配合物光谱特征的几何优化结构模型。在生理 pH 下，有两种 Cu(II)结合模式：4N 和 3NO 平面配位模式；这些模式最好通过不参与水分子在金属离子配体中的配位的模型来描述。相比之下，在较低 pH 值下形成的 2N2O 和 N3O 配位模式涉及轴向水分子的配位。这项研究强调了在模拟 PrP(C)中的铜结合位点时包含显式水分子的重要性。
