Thermodynamics imprinting reveals differential binding of metals to a-synuclein: Relevance to parkinson’s disease

The aggregation of a-synuclein is a hallmark feature of Parkinson’s disease (PD) and other synucleinopathies. Metals are the significant
etiological factors in PD, and their interaction with a-synuclein affect dramatically the kinetics of fibrillation in vitro and are proposed
to play an important and potential neurodegenerative role in vivo. In the present study, we investigated the stoichiometry of
binding of copper [Cu (II)] and iron [Fe (III)] with a-synuclein (wild recombinant type and A30P, A53T, E46K mutant forms) using
isothermal titration calorimetry (ITC). a-Synuclein monomer (wild and mutant forms) titrated by Cu (II), showed two binding sites, with
an apparent KB of 105 M and 104 M, respectively. But, a-synuclein (wild type and mutant forms) titrated with Fe (III) revealed a KB of
105 M with single binding site. The present investigation uncovers the detailed binding propensities between metals and a-synuclein and
has biological implications in PD.