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Dual roles of tau R peptides on Cu(II)/(I)-mediated reactive oxygen species formation

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Abstract

Metal dyshomeostasis plays a critical role in the reactive oxygen species (ROS) formation and protein misfolding and aggregation; hence, contributing to neurodegeneration. Tau protein plays a key role in normal cellular function by maintaining microtubule formation in brain. The role of metal ions on tau protein biochemistry has not been systematically evaluated, but earlier reports indicated that metal ions modulate the complex biochemistry of this protein and its peptides. Herein, we evaluated interactions of biologically-relevant Cu(II) ions with the four repeat peptides of tau protein (R1 through R4) and their role on the formation of ROS, Cu(II) to Cu(I) reduction, and ultimately, peptide aggregation. The role of R peptides on ROS formation was characterized in the absence and presence of biological reducing agent, ascorbate by using UV–Vis and fluorescence spectroscopy. In the presence of the reducing agent, all Cu(II)-peptide complexes reduced hydroxyl radical (OH·), while only Cu(II)-R3 complex depleted the hydrogen peroxide (H2O2). In the absence of a reducing agent, only Cu(II)-R2 and Cu(II)-R3 complexes, which contain Cys and His residues, produced OH· and H2O2. Only R2 and R3 peptides, but not R1 and R4, reduced Cu(II) to Cu(I). The aggregation propensities of R peptides were modulated by Cu(II) and ascorbate, and were imaged by transmission electron microscopy. All metallo-peptides were characterized predominantly as singly charged mononuclear complexes by mass spectrometry. The data indicate that Cu(II)-peptide complexes may act as pro-oxidants or antioxidants and exhibit unique aggregation propensities under specific environmental conditions, with implications in the biological setting.

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Acknowledgements

S.M. thanks Trent University for support and Noblegen for access to their spectrophotometer. This research was partially supported by the NIH NIGMS R15GM11905301 to S.M-M (2016-2018 Oakland University). Dr. Vickie Kimler (Eye Research Institute at Oakland University) and Dr. Alicia Withrow (Michigan State University) are thanked for assistance with TEM imaging. SA acknowledges the Honors College and Provost Undergraduate Research Award at Oakland University for supporting part of this project. We are grateful to Dr. Olena Y. Danylyuk (Mass Spectrometry and Analytical Laboratory, Lumigen Instrument Center, Department of Chemistry, Wayne State University) for MALDI-TOF MS analysis.

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Authors and Affiliations

  1. Department of Forensic Science, Environmental and Life Science Program, Trent University, Peterborough, ON, Canada

    Camilla Golec, Shaelyn Mortensen & Sanela Martic-Milne

  2. Department of Chemistry, Oakland University, Rochester, MI, USA

    Saba Anwar

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  1. Camilla Golec
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Correspondence to Sanela Martic-Milne.

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Golec, C., Mortensen, S., Anwar, S. et al. Dual roles of tau R peptides on Cu(II)/(I)-mediated reactive oxygen species formation. J Biol Inorg Chem 26, 919–931 (2021). https://doi.org/10.1007/s00775-021-01902-7

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