Copper ion incorporation in α-synuclein amyloids
Artikel i vetenskaplig tidskrift, 2024

Copper ion dys-homeostasis is linked to neurodegenerative diseases involving amyloid formation. Even if many amyloidogenic proteins can bind copper ions as monomers, little is known about copper interactions with the resulting amyloid fibers. Here, we investigate copper interactions with α-synuclein, the amyloid-forming protein in Parkinson's disease. Copper (Cu(II)) binds tightly to monomeric α-synuclein in vitro involving the N-terminal amine and the side chain of His50. Using purified protein and biophysical methods in vitro, we reveal that copper ions are readily incorporated into the formed amyloid fibers when present at the start of aggregation reactions, and the metal ions also bind if added to pre-formed amyloids. Efficient incorporation is observed for α-synuclein variants with perturbation of either one of the high-affinity monomer copper-binding residues (i.e., N-terminus or His50) whereas a variant with both N-terminal acetylation and His50 substituted with Ala does not incorporate any copper into the amyloids. Both the morphology of the resulting α-synuclein amyloids (amyloid fiber pitch, secondary structure, proteinase sensitivity) and the copper chemical properties (redox activity, chemical potential) are altered when copper is incorporated into amyloids. We speculate that copper chelation by α-synuclein amyloids contributes to the observed copper dys-homeostasis (e.g., reduced bioavailable levels) in Parkinson's disease patients. At the same time, amyloid-copper interactions may be protective to neuronal cells as they will shield aberrantly free copper ions from promotion of toxic reactive oxygen species.

alpha-synuclein

copper

reactive oxygen species

amyloid

aggregation

Författare

Gulshan Rameshrao Walke

Chalmers, Life sciences, Kemisk biologi

Ranjeet Kumar

Chalmers, Life sciences, Kemisk biologi

Pernilla Wittung Stafshede

Chalmers, Life sciences, Kemisk biologi

Protein Science

0961-8368 (ISSN) 1469896x (eISSN)

Vol. 33 4 e4956

Ämneskategorier

Biokemi och molekylärbiologi

Neurovetenskaper

Biofysik

DOI

10.1002/pro.4956

PubMed

38511511

Mer information

Senast uppdaterat

2024-08-07