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Secondary structure and dynamics of micelle bound - and -synuclein

Department of Biochemistry and Program in Structural Biology, Weill Medical College of Cornell University, New York, New York 10021, USA

(RECEIVED August 23, 2005; FINAL REVISION January 27, 2006; ACCEPTED January 28, 2006)

We have used solution state NMR spectroscopy to characterize the secondary structure and backbone dynamics of the proteins - and -synuclein in their detergent micelle-bound conformations. Comparison of the results with those previously obtained for the Parkinson's disease-linked protein -synuclein shows that structural differences between the three homologous synuclein family members are directly related to variations in their primary amino acid sequences. An 11-residue deletion in the lipid-binding domain of -synuclein leads to the destabilization of an entire segment of the micelle-bound helical structure containing the deletion site. The acidic C-terminal tail region of -synuclein, which displays extensive sequence divergence, is more highly disordered than the corresponding regions in the other two family members. The observed structural differences are likely to mediate functional variations between the three proteins, with differences between - and -synuclein expected to revolve around their lipid interactions, while differences in -synuclein function are expected to result from different protein–protein interactions mediated by its unique C-terminal tail.

Keywords: synuclein; Parkinson's; membrane proteins; amyloid; protein aggregation

Reprint requests to: David Eliezer, Department of Biochemistry and Program in Structural Biology, Weill Medical College of Cornell University, New York, NY 10021, USA; e-mail: dae2005{at}med.cornell.edu; fax: (212) 746-4843.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051803606.

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