A relationship between the transient structure in the monomeric state and the aggregation propensities of α-synuclein and β-synuclein.
α-Synuclein is an intrinsically disordered protein whose aggregation is implicated in Parkinson's disease. A second member of the synuclein family, β-synuclein, shares significant sequence similarity with α-synuclein but is much more resistant to aggregation. β-Synuclein is missing an 11-residue stretch in the central non-β-amyloid component region that forms the core of α-synuclein amyloid fibrils, yet insertion of these residues into β-synuclein to produce the βSHC construct does not markedly increase the aggregation propensity. To investigate the structural basis of these different behaviors, quantitative nuclear magnetic resonance data, in the form of paramagnetic relaxation enhancement-derived interatomic distances, are combined with molecular dynamics simulations to generate ensembles of structures representative of the solution states of α-synuclein, β-synuclein, and βSHC. Comparison of these ensembles reveals that the differing aggregation propensities of α-synuclein and β-synuclein are associated with differences in the degree of residual structure in the C-terminus coupled to the shorter separation between the N- and C-termini in β-synuclein and βSHC, making protective intramolecular contacts more likely.
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
Jane R
JR
Allison
Robert C
RC
Rivers
John C
JC
Christodoulou
Michele
M
Vendruscolo
Christopher M
CM
Dobson
D000595:Amino Acid Sequence; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D051844:alpha-Synuclein / Q000737:chemistry* / Q000648:ultrastructure; D051846:beta-Synuclein / Q000737:chemistry* / Q000648:ultrastructure
D066329:Protein Aggregates; D051844:alpha-Synuclein; D051846:beta-Synuclein