Structure and topology of the non-amyloid-beta component fragment of human alpha-synuclein bound to micelles: implications for the aggregation process.
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.
Bisaglia
Marco
M
Department of Chemical Sciences, University of Padova, 35131 Padova, Italy.
Trolio
Alessandra
A
Bellanda
Massimo
M
Bergantino
Elisabetta
E
Bubacco
Luigi
L
Mammi
Stefano
S
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
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