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

Horvath, Istvan,1979Chalmers tekniska högskola,Chalmers University of Technology (författare)

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.

Blockhuys, Stephanie,1983Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)steblo (författare)
Šulskis, DariusGöteborgs universitet,University of Gothenburg (författare)
Holgersson, Stellan,1964Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)stehol (författare)
Kumar, Ranjeet,1980Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)ranjeet (författare)
Burmann, Björn M.Göteborgs universitet,University of Gothenburg (författare)
Wittung Stafshede, Pernilla,1968Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)perwit (författare)
Chalmers tekniska högskolaGöteborgs universitet (creator_code:org_t)

Ingår i:ACS Chemical Neuroscience: American Chemical Society (ACS)10:11, s. 4659-46681948-7193

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