Differential copper binding to alpha-synuclein and its disease-associated mutants affect the aggregation and amyloid formation

The binding of Cu2 + to α-Syn occurs at three binding sites with a higher affinity for region 48-53. In case of the familial mutant H50Q, the single point mutation resulted in the abolishment of Cu2 + binding site in the region 48-53. However, binding at the N- (3-11) and C- (115-123) terminus was found to be similar to the WT. The binding of Cu2 + to the familial mutant G51D was found to be comparable to the WT. In all the synucleins, an increased rate of fibril formation was observed in the presence of Cu2 + with the release of long-range contacts between the N- and C- terminus. Even though the binding of Cu2 + to the mutant H50Q was less, it showed the formation of the fibrils at an early stage suggesting that the involvement of region 48-53 in Cu2 + binding is not responsible for enhancing the fibril formation.174