Structural Models for Cu(II) Bound to the Fragment 92鈥?6 of the Human Prion Protein

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• 作者：Rafael Grande-Aztatzi ; Lina Rivillas-Acevedo ; Liliana Quintanar ; Alberto Vela
• 刊名：The Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：January 24, 2013
• 年：2013
• 卷：117
• 期：3
• 页码：789-799
• 全文大小：677K
• 年卷期：v.117,no.3(January 24, 2013)
• ISSN：1520-5207

文摘

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鈥搗is 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鈥?6) 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.