title: Characterization of alpha-synuclein interactions with selected aggregation-inhibiting small molecules.
abstract: The 140-residue protein alpha-synuclein (aS) has been implicated in the molecular chain of events leading to Parkinson's disease, which relates to the hierarchical aggregation of aS into soluble oligomers and insoluble fibrils. A number of small organic molecules have been reported to inhibit aS aggregation. Here, the interactions of chlorazole black E, Congo red, lacmoid, PcTS-Cu (2+), and rosmarinic acid with aS are examined by NMR spectroscopy to identify aS sequence elements that are masked by these compounds. Surprisingly, similar aS interaction sites, encompassing residues 3-18 and 38-51, were obtained for all molecules at equimolar small molecule:aS ratios. At higher ratios, virtually the entire amphiphilic region of aS (residues 2-92) is affected, revealing the presence of additional, lower affinity interaction sites. Upon rearranging the high-affinity interaction sites over the aS amphiphilic region in an aS mutant form, perturbations of the entire amphiphilic region were found to have already been obtained at equimolar ratios, indicating a high specificity for the original binding sites. CD spectroscopy reveals that, in the presence of the small molecules, the aS structure is still dominated by random-coil characteristics. The strongest effects are exerted by molecules that contain sulfonate groups adjacent to aromatic systems, often present in multiple copies in a symmetrical arrangement, suggesting that these elements are useful for developing an aS-specific chemical chaperone.
authors: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90033, USA.
authors: Jampani Nageswara
authors: JN
authors: Rao
authors: Varun
authors: V
authors: Dua
authors: Tobias S
authors: TS
authors: Ulmer
mesh_terms: D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D009930:Organic Chemicals; D051844:alpha-Synuclein