title: Evolutionary aspects of the synuclein super-family and sub-families based on large-scale phylogenetic and group-discrimination analysis.
abstract: Over the last decade, many genetic studies have suggested that the synucleins, which are small, natively unfolded proteins, are closely related to Parkinson's disease and cancer. Less is known about the molecular basis of this role. A comprehensive analysis of the evolutionary path of the synuclein protein family may reveal the relationship between evolutionarily conserved residues and protein function or structure. The phylogeny of 252 unique synuclein sequences from 73 organisms suggests that gamma-synuclein is the common ancestor of alpha- and beta-synuclein. Although all three sub-families remain highly conserved, especially at the N-terminal, nearly 15% of the residues in each sub family clearly diverged during evolution, providing crucial guidance for investigations of the different properties of the members of the superfamily. His50 is found to be an alpha-specific conserved residue (91%) and, based on mutagenesis, evolutionarily developed a secondary copper binding site in the alpha synuclein family. Surprisingly, this site is located between two well-known polymorphisms of alpha-synuclein, E46K and A53T, which are linked to early-onset Parkinson's disease, suggesting that the mutation-induced impairment of copper binding could be a mechanism responsible for alpha-synuclein aggregation.
authors.affiliation: Department of Neurology, Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University, Shanghai 200233, China.
authors.forename: Jiawen
authors.initials: J
authors.lastname: Yuan
authors.forename: Yuwu
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D003300:Copper / Q000737:chemistry; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D051844:alpha-Synuclein / Q000737:chemistry / Q000145:classification* / Q000235:genetics; D051846:beta-Synuclein / Q000737:chemistry / Q000145:classification* / Q000235:genetics; D051845:gamma-Synuclein / Q000737:chemistry / Q000145:classification* / Q000235:genetics
chemical_list: D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein; D003300:Copper
keywords: His50; Parkinson’s disease; Phylogenetic tree; Synuclein