Binding Interactions of Agents That Alter ?-Synuclein Aggregation.

ABSTRACT: Further examination of peptides with well-folded antiparallel ? strands as inhibitors of amyloid formation from ?-synuclein has resulted in more potent inhibitors. Several of these had multiple Tyr residues and represent a new lead for inhibitor design by small peptides that do not divert ?-synuclein to non-amyloid aggregate formation. The most potent inhibitor obtained in this study is a backbone cyclized version of a previously studied ? hairpin, designated as WW2, with a cross-strand Trp/Trp cluster. The cyclization was accomplished by adding a d-Pro-l-Pro turn locus across strand termini. At a 2:1 peptide to ?-synuclein ratio, cyclo-WW2 displays complete inhibition of ?-structure formation. Trp-bearing antiparallel ?-sheets held together by a disulphide bond are also potent inhibitors. 15N HSQC spectra of ?-synuclein provided new mechanistic details. The time course of 15N HSQC spectral changes observed during ?-oligomer formation has revealed which segments of the structure become part of the rigid core of an oligomer at early stages of amyloidogenesis and that the C-terminus remains fully flexible throughout the process. All of the effective peptide inhibitors display binding-associated titration shifts in 15N HSQC spectra of ?-synuclein in the C-terminal Q109-E137 segment. Cyclo-WW2, the most potent inhibitor, also displays titration shifts in the G41-T54 span of ?-synuclein, an additional binding site. The earliest aggregation event appears to be centered about H50 which is also a binding site for our most potent inhibitor.

SUBMITTER: Sivanesam K 

PROVIDER: S-EPMC4332700 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature