title: Conformational Compatibility Is Essential for Heterologous Aggregation of α-Synuclein.
abstract: Under aggregation-prone conditions, soluble amyloidogenic protein monomers can self-assemble into fibrils or they can fibrillize on preformed fibrillar seeds (seeded aggregation). Seeded aggregations are known to propagate the morphology of the seeds in the event of cross-seeding. However, not all proteins are known to cross-seed aggregation. Cross-seeding has been proposed to be restricted either because of differences in the protein sequences or because of conformations between the seeds and the soluble monomers. Here, we examine cross-seeding efficiency between three α-synuclein sequences, wild-type, A30P, and A53T, each varying in only one or two amino acids but forming morphologically distinct fibrils. Results from bulk Thioflavin-T measurements, monomer incorporation quantification, single fibril fluorescence microscopy, and atomic force microscopy show that under the given solution conditions conformity between the conformation of seeds and monomers is essential for seed elongation. Moreover, elongation characteristics of the seeds are defined by the type of seed.
authors.forename: Arshdeep
authors.initials: A
authors.lastname: Sidhu
authors.forename: Ine
authors.initials: I
authors.lastname: Segers-Nolten
authors.affiliation: Vrije Universiteit Amsterdam , De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Subramaniam
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D052160:Benzothiazoles; D002942:Circular Dichroism / Q000379:methods; D006801:Humans; D018625:Microscopy, Atomic Force; D008968:Molecular Conformation; D013844:Thiazoles / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T
keywords: Seed and monomer conformation; heterologous seeding; sequence similarity; templating; two-color fluorescence microscopy; α-synuclein