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

protein-protein interaction

α-Synuclein

Parkinson's disease

nuclear magnetic resonance

Atox1

Författare

Istvan Horvath

Chalmers, Biologi och bioteknik, Kemisk biologi

Stephanie Blockhuys

Chalmers, Biologi och bioteknik, Kemisk biologi

Darius Šulskis

Göteborgs universitet

Wallenberg Lab.

Stellan Holgersson

Chalmers, Kemi och kemiteknik, Energi och material, Kärnkemi

Ranjeet Kumar

Chalmers, Biologi och bioteknik, Kemisk biologi

Björn M. Burmann

Göteborgs universitet

Wallenberg Lab.

Pernilla Wittung Stafshede

Chalmers, Biologi och bioteknik, Kemisk biologi

ACS Chemical Neuroscience

1948-7193 (ISSN)

Vol. In press

Ämneskategorier

Biokemi och molekylärbiologi

Biofysik

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.1021/acschemneuro.9b00476

PubMed

31600047

Mer information

Senast uppdaterat

2019-11-08