Molecular determinants of the aggregation behavior of alpha- and beta-synuclein.
Alpha- and beta-synuclein are closely related proteins, the first of which is associated with deposits formed in neurodegenerative conditions such as Parkinson's disease while the second appears to have no relationship to any such disorders. The aggregation behavior of alpha- and beta-synuclein as well as a series of chimeric variants were compared by exploring the structural transitions that occur in the presence of a widely used lipid mimetic, sodium dodecyl sulfate (SDS). We found that the aggregation rates of all these protein variants are significantly enhanced by low concentrations of SDS. In particular, we inserted the 11-residue sequence of mainly hydrophobic residues from the non-amyloid-beta-component (NAC) region of alpha-synuclein into beta-synuclein and show that the fibril formation rate of this chimeric protein is only weakly altered from that of beta-synuclein. These intrinsic propensities to aggregate are rationalized to a very high degree of accuracy by analysis of the sequences in terms of their associated physicochemical properties. The results begin to reveal that the differences in behavior are primarily associated with a delicate balance between the positions of a range of charged and hydrophobic residues rather than the commonly assumed presence or absence of the highly aggregation-prone region of the NAC region of alpha-synuclein. This conclusion provides new insights into the role of alpha-synuclein in disease and into the factors that regulate the balance between solubility and aggregation of a natively unfolded protein.
Rivers
Robert C
RC
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Kumita
Janet R
JR
Tartaglia
Gian Gaetano
GG
Dedmon
Matthew M
MM
Pawar
Amol
A
Vendruscolo
Michele
M
Dobson
Christopher M
CM
Christodoulou
John
J
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D019906:Nuclear Magnetic Resonance, Biomolecular; D010300:Parkinson Disease / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D017384:Sequence Deletion; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D012995:Solubility; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics; D051846:beta-Synuclein / Q000737:chemistry* / Q000235:genetics
D016229:Amyloid beta-Peptides; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D012967:Sodium Dodecyl Sulfate