Cu(II) and dopamine bind to α-synuclein and cause large conformational changes

Area of Science:

• Neuroscience
• Biochemistry
• Biophysics

Background:

• Alpha-synuclein (AS) aggregation forms Lewy bodies, a hallmark of Parkinson's disease.
• Understanding AS interactions is crucial for Parkinson's disease research.

Purpose of the Study:

• To investigate the binding of Cu(II) and dopamine to AS.
• To elucidate the structural changes induced by dopamine binding to AS.

Main Methods:

• Nanopore analysis using α-hemolysin.
• Circular Dichroism (CD) spectroscopy.
• Isothermal Titration Calorimetry (ITC).
• Two-dimensional Nuclear Magnetic Resonance (2D NMR) spectroscopy.

Main Results:

• Cu(II) binds to the N-terminus of AS, hindering translocation through a nanopore.
• Dopamine binding alters AS translocation events and affects N- and C-terminal peptides.
• Dopamine induces partial folding of AS, confirmed by NMR and ITC, suggesting interaction with both termini.

Conclusions:

• Dopamine interaction with AS leads to structural changes and partial folding.
• These dopamine-induced partially folded AS conformations may be critical intermediates in AS misfolding and fibrillization.
• Findings provide insights into the early stages of Parkinson's disease pathogenesis.