title: Structure and topology of the non-amyloid-beta component fragment of human alpha-synuclein bound to micelles: implications for the aggregation process.
abstract: Human alpha-synuclein is a small soluble protein abundantly expressed in neurons. It represents the principal constituent of Lewy bodies, the main neuropathological characteristic of Parkinson's disease. The fragment corresponding to the region 61-95 of the protein, originally termed NAC (non-amyloid-beta component), has been found in amyloid plaques associated with Alzheimer's disease, and several reports suggest that this region represents the critical determinant of the fibrillation process of alpha-synuclein. To better understand the aggregation process of alpha-synuclein and the role exerted by the biological membranes, we studied the structure and the topology of the NAC region in the presence of SDS micelles, as membrane-mimetic environment. To overcome the low solubility of this fragment, we analyzed a recombinant polypeptide corresponding to the sequence 57-102 of alpha-synuclein, which includes some charged amino acids flanking the NAC region. Three distinct helices are present, separated by two flexible stretches. The first two helices are located closer to the micelle surface, whereas the last one seems to penetrate more deeply into the micelle. On the basis of the structural and topological results presented, a possible pathway for the aggregation process is suggested. The structural information described in this work may help to identify the appropriate target to reduce the formation of pathological alpha-synuclein aggregation.
authors.affiliation: Department of Chemical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bisaglia
authors.forename: Alessandra
authors.initials: A
authors.lastname: Trolio
authors.forename: Massimo
authors.initials: M
authors.lastname: Bellanda
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bergantino
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.forename: Stefano
authors.initials: S
authors.lastname: Mammi
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry; D002942:Circular Dichroism; D003902:Detergents / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D003902:Detergents; D008823:Micelles; D010446:Peptide Fragments; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D010767:Phosphorylcholine; D012967:Sodium Dodecyl Sulfate; C028810:dodecylphosphocholine