title: The N-terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation.
abstract: α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson's disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43-140) and C-terminally (1-95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA:α-syn oligomers, albeit 1-95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43-140 protein, we analysed the structural characteristics of the DA:α-syn 43-140 dimer and α-syn 43-140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers.
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria, 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia.
authors: Su Ling
authors: SL
authors: Leong
authors: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia; School of Chemistry, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia.
authors: Mark G
authors: MG
authors: Hinds
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria, 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia.
authors: Andrea R
authors: AR
authors: Connor
authors: Biomedical Research Centre, Sheffield Hallam University, Sheffield, S1 1WB, United Kingdom.
authors: David P
authors: DP
authors: Smith
authors: Biomedical Research Centre, Sheffield Hallam University, Sheffield, S1 1WB, United Kingdom.
authors: Eva
authors: E
authors: Illes-Toth
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria, 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia.
authors: Chi L L
authors: CL
authors: Pham
authors: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia; Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia; Department of Pharmacology, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia.
authors: Kevin J
authors: KJ
authors: Barnham
authors: Department of Pathology, The University of Melbourne, Parkville, Victoria, 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Melbourne, Victoria, 3010, Australia.
authors: Roberto
authors: R
authors: Cappai
mesh_terms: D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D059748:Proteolysis; D012995:Solubility; D014357:Trypsin / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D051844:alpha-Synuclein; D014357:Trypsin; D004298:Dopamine