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Interaction between Hemin and Prion Peptides: Binding, Oxidative Reactivity and Aggregation.

ABSTRACT: We investigate the interaction of hemin with four fragments of prion protein (PrP) containing from one to four histidines (PrP106-114, PrP95-114, PrP84-114, PrP76-114) for its potential relevance to prion diseases and possibly traumatic brain injury. The binding properties of hemin-PrP complexes have been evaluated by UV-visible spectrophotometric titration. PrP peptides form a 1:1 adduct with hemin with affinity that increases with the number of histidines and length of the peptide; the following log K1 binding constants have been calculated: 6.48 for PrP76-114, 6.1 for PrP84-114, 4.80 for PrP95-114, whereas for PrP106-114, the interaction is too weak to allow a reliable binding constant calculation. These constants are similar to that of amyloid-? (A?) for hemin, and similarly to hemin-A?, PrP peptides tend to form a six-coordinated low-spin complex. However, the concomitant aggregation of PrP induced by hemin prevents calculation of the K2 binding constant. The turbidimetry analysis of [hemin-PrP76-114] shows that, once aggregated, this complex is scarcely soluble and undergoes precipitation. Finally, a detailed study of the peroxidase-like activity of [hemin-(PrP)] shows a moderate increase of the reactivity with respect to free hemin, but considering the activity over long time, as for neurodegenerative pathologies, it might contribute to neuronal oxidative stress.

SUBMITTER: Dell'Acqua S

PROVIDER: S-EPMC7589926 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Interaction between Hemin and Prion Peptides: Binding, Oxidative Reactivity and Aggregation.

Dell'Acqua Simone S Massardi Elisa E Monzani Enrico E Di Natale Giuseppe G Rizzarelli Enrico E Casella Luigi L

International journal of molecular sciences 20201013 20

We investigate the interaction of hemin with four fragments of prion protein (PrP) containing from one to four histidines (PrP106-114, PrP95-114, PrP84-114, PrP76-114) for its potential relevance to prion diseases and possibly traumatic brain injury. The binding properties of hemin-PrP complexes have been evaluated by UV-visible spectrophotometric titration. PrP peptides form a 1:1 adduct with hemin with affinity that increases with the number of histi ...[more]

PMID: 33066163

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Project description:Prion protein aggregation is known to be modulated by macromolecules including nucleic acids. To clarify the role of nucleic acids in PrP pathology, we investigated the interaction between nucleic acids and the prion peptide (PrP)-a synthetic prion protein model peptide resembling a portion of the human prion protein in structure and function spanning amino acid residues 106-126. We used synthetic DNA lattices and natural DNA duplexes extracted from salmon (sDNA) bound with PrP and studied their interaction using distinct physical measurements. The formation of DNA lattices with PrP was visualized by atomic force microscopy (AFM) to investigate the influence of the PrP. PrP inhibited the growth of the double-crossover (DX) lattices significantly compared to the control peptide (CoP). We also conducted optical measurements such as ultraviolet-visible (UV-Vis), circular dichroism (CD), and Fourier transform infrared (FTIR) spectroscopies to validate the interaction between PrP and DNA immediately (D0) and after a 30-day incubation (D30) period. UV-Vis spectra showed variation in the absorbance intensities, specific for the binding of CoP and PrP to DNA. The CD analysis revealed the presence of various secondary structures, such as α-helices and β-sheets, in PrP- and PrP-bound sDNA complexes. The PrP-sDNA interaction was confirmed using FTIR by the change and shift of the absorption peak intensity and the alteration of PrP secondary structures in the presence of DNA. The cytotoxic effects of the PrP-bound sDNA complexes were assessed by a cytotoxicity assay in human neuroblastoma cells in culture. It confirmed that PrP with sDNA was less cytotoxic than CoP. This study provides new applications for DNA molecules by investigating their effect in complex with aggregated proteins. Our study unequivocally showed the beneficial effect of the interaction between DNA and the pathological prion protein. It therefore provides valuable information to exploit this effect in the development of potential therapeutics. Moreover, our work might serve as a basis for further studies investigating the role of DNA interactions with other amyloidogenic proteins.

Dataset Information

Interaction between Hemin and Prion Peptides: Binding, Oxidative Reactivity and Aggregation.

Publications

Interaction between Hemin and Prion Peptides: Binding, Oxidative Reactivity and Aggregation.

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