Integrative Structure Models and Local Structural Dynamics of the unbound α-Synuclein monomer Conformations
2Department of Pharmacology, Penn State College of Medicine, USA
The structure-function relationship in proteins is challenged by proteins with intrinsic disorder. However, binding stabilizing specific folded structures paves possible routes to explain IDPs functionality under the structure-function paradigm. α-Synuclein (α-syn) is an intrinsically disordered protein well known for its implications in Parkinson`s Disease. α-Syn has been documented to undergo folding upon attaching to the surfaces of negatively-charged membranes into a helical form. However, α-syn is capable to self-associate and form other folded structures, including ones involving beta-sheets. Are these folding capabilities encoded in the collection of conformations of the unbound monomeric α-syn, and are these conformations stable enough to simply be stabilized following initial binding recognition?
Using experimental results and structural modeling we identify conformations of the unbound α-syn monomer, characterize their structural features and identify some as having high spatial homology to bound-induced folded forms of α-syn. Then, by performing single-molecule protein-induced fluorescence enhancement to probe the structural dynamics of local structures within 0-3 nm of specific residues we show that α-syn has multiple local structure sub-populations, with transitions between them occurring in tens of milliseconds or slower. This, taken with previous single-molecule FRET measurements of local structural dynamics in α-syn provides a complete picture of the unbound α-syn monomer - contains several structurally-distinct conformational states, some resembling the final folded states post binding, with rapid nonlocal conformational dynamics, but relatively stable local structures. We speculate that these stable local structural motifs may act as binding recognition motifs, to initiate the stabilization of the bound-folded state.