Article

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

The University of Melbourne Department of Pathology Victoria 3010 Australia; The University of Melbourne Neuroproteomics Platform, National Neuroscience Facility, The Bio21 Molecular Science and Biotechnology Institute Victoria 3010 Australia; The University of Melbourne Mental Health Research Institute Victoria 3010 Australia; Monash University School of Physics Victoria 3800 Australia; The University of Melbourne Centre for Neuroscience Victoria 3010 Australia
Applied Magnetic Resonance (impact factor: 0.75). 05/2012; 36(2):223-229. DOI:10.1007/s00723-009-0020-8 pp.223-229

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.

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Keywords

A53T mutants
 
amino terminus
 
coordination modes
 
Cu2+ coordination
 
Cu2+ coordination modes
 
electron paramagnetic resonance spectroscopy
 
familial mutants
 
familial mutations
 
mode 1
 
modes 1
 
native Cu2+ coordination modes
 
native Cu2+/αS complex
 
physiological pH
 
protein backbone
 
recombinant human αS
 
relative proportion
 
side chain
 
small natively unfolded protein
 
structural changes
 
α-Synuclein