A Four-Amino Acid Linker between Repeats in the α-Synuclein Sequence Is Important for Fibril Formation

alpha-Synuclein is a 140-amino acid protein that can switch conformation among intrinsically disordered in solution, helical on a membrane, and beta-sheet in amyloid fibrils. Using the fluorescence of single-tryptophan mutants, we determined the immersion of different regions of the protein into lipid membranes. Our results suggest the presence of a flexible break close to residues 52-55 between two helical domains. The four-amino acid linker is. not,necessary for membrane binding;hilt is important for fibril formation. A deletion mutant lacking. this linker aggregates extremely slowly and slightly inhibits wild-type aggregation, possibly by blocking the growing ends of fibrils.