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A soluble α-synuclein construct forms a dynamic tetramer

Wang, Wei, Perovic, Iva, Chittuluru, Johnathan, Kaganovich, Alice, Nguyen, Linh T. T., Liao, Jingling, Auclair, Jared R., Johnson, Derrick, Landeru, Anuradha, Simorellis, Alana K., Ju, Shulin, Cookson, Mark R., Asturias, Francisco J., Agar, Jeffrey N., Webb, Brian N., Kang, ChulHee, Ringe, Dagmar, Petsko, Gregory A., Pochapsky, Thomas C., Hoang, Quyen Q.
Proceedings of the National Academy of Sciences of the United States of America 2011 v.108 no.43 pp. 17797-17802
crosslinking, humans, hydrophobicity, lipid bilayers, micelles, models, nuclear magnetic resonance spectroscopy, phospholipids, phosphorus
A heterologously expressed form of the human Parkinson disease-associated protein α-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid bilayers or micelles. Sequential NMR assignments, intramonomer nuclear Overhauser effects, and circular dichroism spectra are consistent with transient formation of α-helices in the first 100 N-terminal residues of the 140-residue α-synuclein sequence. Total phosphorus analysis indicates that phospholipids are not associated with the tetramer as isolated, and chemical cross-linking experiments confirm that the tetramer is the highest-order oligomer present at NMR sample concentrations. Image reconstruction from electron micrographs indicates that a symmetric oligomer is present, with three- or fourfold symmetry. Thermal unfolding experiments indicate that a hydrophobic core is present in the tetramer. A dynamic model for the tetramer structure is proposed, based on expected close association of the amphipathic central helices observed in the previously described micelle-associated "hairpin" structure of α-synuclein.