Residual Structure, Backbone Dynamics, and Interactions within the Synuclein Family

The human synuclein protein family includes α-synuclein, which has been linked to both familial and sporadic Parkinson's disease, and the highly homologous β and γ-synuclein. Mutations in α-synuclein cause autosomal dominant early onset Parkinson's, and the protein is found deposited in a fibrillar form in hereditary and idiopathic forms of the disease. No genetic link between β and γ-synuclein, and any neurodegenerative disease has been established, and it is generally considered that these proteins are not highly pathogenic. In addition, β and γ-synuclein are reported to aggregate less readily than α-synuclein in vitro. Indeed, β-synuclein has been reported to protect against α-synuclein aggregation in vitro, as well as α-synuclein-mediated toxicity in vivo. Earlier, we compared the structural properties of the highly helical states adopted by all three synucleins in association with detergent micelles in an attempt to delineate the basis for functional differences between the three proteins. Here, we report a comparison of the structural and dynamic properties of the free states of all three proteins in order to shed light on differences that may help to explain their different propensities to aggregate, which in turn may underlie their differing contributions to the etiology of Parkinson's disease. We find that γ-synuclein closely resembles α-synuclein in its free-state residual secondary structure, consistent with the more similar propensities of the two proteins to aggregate in vitro. β-Synuclein, however, differs significantly from α-synuclein, exhibiting a lower predisposition towards helical structure in the second half of its lipid-binding domain, and a higher preference for extended structures in its C-terminal tail. Both β and γ-synuclein show less extensive transient long-range structure than that observed in α-synuclein. These results raise questions regarding the role of secondary structure propensities and transient long-range contacts in directing synuclein aggregation reactions.