Structural basis for dityrosine-mediated inhibition of alpha-synuclein fibrillation

• α-synuclein (aSyn) is a small intrinsically disordered protein which can self-assemble into highly organized β-sheet structures that are found to accumulate in plaques in the brain of Parkinson’s Disease patients. Oxidative stress has been shown to be important for aSyn and its self-assembly. Here we characterize the molecular and structural effects that mild oxidation has on aSyn monomer and its aggregation. Using a combination of biophysical methods, SAXS and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages that reduce aSyn’s size by a factor of √2. MD simulations support our experimental results showing a stable and compact aSyn conformation that prevents self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation. 

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

Parkinson’s Disease

Disorder

amyloid

dityrosine crosslinks

metal catalyzed oxidation

Biokemi

Biochemistry

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)