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Combined EXAFS and DFT structure calculations provide structural insights into the 1:1 multi-histidine complexes of Cu(II) , Cu(I) , and Zn(II) with the tandem octarepeats of the mammalian prion protein.

ABSTRACT: The metal-coordinating properties of the prion protein (PrP) have been the subject of intense focus and debate since the first reports of its interaction with copper just before the turn of the century. The picture of metal coordination to PrP has been improved and refined over the past decade, but structural details of the various metal coordination modes have not been fully elucidated in some cases. In the present study, we have employed X-ray absorption near-edge spectroscopy as well as extended X-ray absorption fine structure (EXAFS) spectroscopy to structurally characterize the dominant 1:1 coordination modes for Cu(II) , Cu(I) , and Zn(II) with an N-terminal fragment of PrP. The PrP fragment corresponds to four tandem repeats representative of the mammalian octarepeat domain, designated as OR4 , which is also the most studied PrP fragment for metal interactions, making our findings applicable to a large body of previous work. Density functional theory (DFT) calculations have provided additional structural and thermodynamic data, and candidate structures have been used to inform EXAFS data analysis. The optimized geometries from DFT calculations have been used to identify potential coordination complexes for multi-histidine coordination of Cu(II) , Cu(I) , and Zn(II) in an aqueous medium, modelled using 4-methylimidazole to represent the histidine side chain. Through a combination of in silico coordination chemistry as well as rigorous EXAFS curve-fitting, using full multiple scattering on candidate structures derived from DFT calculations, we have characterized the predominant coordination modes for the 1:1 complexes of Cu(II) , Cu(I) , and Zn(II) with the OR4 peptide at pH?7.4 at atomic resolution, which are best represented as square-planar [Cu(II) (His)4 ](2+) , digonal [Cu(I) (His)2 ](+) , and tetrahedral [Zn(II) (His)3 (OH2 )](2+) , respectively.

SUBMITTER: Pushie MJ

PROVIDER: S-EPMC4287235 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Project description:Copper coordination to the prion protein (PrP) has garnered considerable interest for almost 20 years, due in part to the possibility that this interaction may be part of the normal function of PrP. The most characterized form of copper binding to PrP has been Cu(2+) interaction with the conserved tandem repeats in the N-terminal domain of PrP, termed the octarepeats, with many studies focusing on single and multiple repeats of PHGGGWGQ. Extended X-ray absorption fine structure (EXAFS) spectroscopy has been used in several previous instances to characterize the solution structure of Cu(2+) binding into the peptide backbone in the HGGG portion of the octarepeats. All previous EXAFS studies, however, have benefitted from crystallographic structure information for [Cu(II) (Ac-HGGGW-NH2)(-2H)] but have not conclusively demonstrated that the complex EXAFS spectrum represents the same coordination environment for Cu(2+) bound to the peptide backbone. Density functional structure calculations as well as full multiple scattering EXAFS curve fitting analysis are brought to bear on the predominant coordination mode for Cu(2+) with the Ac-PHGGGWGQ-NH2 peptide at physiological pH, under high Cu(2+) occupancy conditions. In addition to the structure calculations, which provide a thermodynamic link to structural information, methods are also presented for extensive deconvolution of the EXAFS spectrum. We demonstrate how the EXAFS data can be analyzed to extract the maximum structural information and arrive at a structural model that is significantly improved over previous EXAFS characterizations. The EXAFS spectrum for the chemically reduced form of copper binding to the Ac-PHGGGWGQ-NH2 peptide is presented, which is best modeled as a linear two-coordinate species with a single His imidazole ligand and a water molecule. The extent of in situ photoreduction of the copper center during standard data collection is also presented, and EXAFS curve fitting of the photoreduced species reveals an intermediate structure that is similar to the Cu(2+) form with reduced coordination number.

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Combined EXAFS and DFT structure calculations provide structural insights into the 1:1 multi-histidine complexes of Cu(II) , Cu(I) , and Zn(II) with the tandem octarepeats of the mammalian prion protein.

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