Copper Coordination by Familial Mutants of Parkinson’s Disease-Associated α-Synuclein

Abstract

α-Synuclein (αS) is a small natively unfolded protein whose interactions with Cu²⁺ have been proposed to play a role in Parkinson’s disease (PD). We recently studied the Cu²⁺ coordination of recombinant human αS using electron paramagnetic resonance spectroscopy and identified two coordination modes at physiological pH, one anchored upon the amino terminus (mode 1) and the other anchored upon the side chain of His50 (mode 2). Here we report the Cu²⁺ coordination of the A30P, E46K and A53T mutants associated with inherited forms of PD. At physiological pH, the same two Cu²⁺ coordination modes were adopted by each of the familial mutants. The spectrum of Cu²⁺/αS(A53T) was very similar to the spectrum of the native Cu²⁺/αS complex; however, mode 2 coordination was marginally higher in the spectrum of Cu²⁺/αS(E46K) and considerably more favored in the Cu²⁺/αS(A30P) complex. The alteration in only the relative proportion of modes 1 and 2 suggests the familial mutations introduce structural changes of the protein backbone that indirectly affect the stability, but not the identity, of the native Cu²⁺ coordination modes.