A soluble α-synuclein construct forms a dynamic tetramer
2011
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.
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.
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