Interaction between Copper Chaperone Atox1 and Parkinson's Disease Protein α-Synuclein Includes Metal-Binding Sites and Occurs in Living Cells
Journal article, 2019

Alterations in copper ion homeostasis appear coupled to neurodegenerative disorders, but mechanisms are unknown. The cytoplasmic copper chaperone Atox1 was recently found to inhibit amyloid formation in vitro of α-synuclein, the amyloidogenic protein in Parkinson's disease. As α-synuclein may have copper-dependent functions, and free copper ions promote α-synuclein amyloid formation, it is important to characterize the Atox1 interaction with α-synuclein on a molecular level. Here we applied solution-state nuclear magnetic resonance spectroscopy, with isotopically labeled α-synuclein and Atox1, to define interaction regions in both proteins. The α-synuclein interaction interface includes the whole N-terminal part up to Gln24; in Atox1, residues around the copper-binding cysteines (positions 11-16) are mostly perturbed, but additional effects are also found for residues elsewhere in both proteins. Because α-synuclein is N-terminally acetylated in vivo, we established that Atox1 also inhibits amyloid formation of this variant in vitro, and proximity ligation in human cell lines demonstrated α-synuclein-Atox1 interactions in situ. Thus, this interaction may provide the direct link between copper homeostasis and amyloid formation in vivo.

proximity ligation assay

Parkinson's disease

Atox1

protein-protein interaction

nuclear magnetic resonance

α-Synuclein

Author

Istvan Horvath

Chalmers, Biology and Biological Engineering, Chemical Biology

Stephanie Blockhuys

Chalmers, Biology and Biological Engineering, Chemical Biology

Darius Šulskis

University of Gothenburg

Wallenberg Lab.

Stellan Holgersson

Chalmers, Chemistry and Chemical Engineering, Energy and Material, Nuclear Chemistry

Ranjeet Kumar

Chalmers, Biology and Biological Engineering, Chemical Biology

Björn M. Burmann

University of Gothenburg

Wallenberg Lab.

Pernilla Wittung Stafshede

Chalmers, Biology and Biological Engineering, Chemical Biology

ACS Chemical Neuroscience

1948-7193 (ISSN)

Vol. 10 11 4659-4668

Subject Categories

Biochemistry and Molecular Biology

Biophysics

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

DOI

10.1021/acschemneuro.9b00476

PubMed

31600047

More information

Latest update

4/23/2020