title: Creation of aggregation-defective α-synuclein variants by engineering the sequence connecting β-strand-forming domains.
abstract: The aggregation of α-synuclein (αS), which is implicated in the pathology of Parkinson's disease, produces fibrils in which layers of parallel, in-register β-sheet-loop-β-sheets are formed. The effects of sequence variation in the loop-forming region (referred to as the linker region) on αS aggregation have yet to be systematically studied. In the study described here, we created and characterized αS variants containing mutations in the linker regions. Our results indicate that although the physicochemical properties of the linker region, evaluated based on an intrinsic property of a single amino acid, still play a significant role in aggregation, additional factors can also determine aggregation of αS linker mutants. Our analyses suggest that these factors include a pairwise potential for parallel in-register β-sheet formation. A linker variant displaying significantly reduced self-aggregation interfered with αS aggregation by inhibiting the conversion of αS soluble species to αS insoluble fibrils. We anticipate that linker mutations could serve as a novel method of creating αS variants that are aggregation-defective and/or inhibit αS aggregation.
authors: Othmer-Jacobs Department of Chemical and Biological Engineering, Polytechnic Institute of New York University, 6 MetroTech Center, Brooklyn, NY 11201, USA.
authors: Michael
authors: M
authors: Hernandez
authors: Sofia
authors: S
authors: Golbert
authors: Li Guo
authors: LG
authors: Zhang
authors: Jin Ryoun
authors: JR
authors: Kim
mesh_terms: D000595:Amino Acid Sequence; D008855:Microscopy, Electron, Scanning; D008969:Molecular Sequence Data; D009154:Mutation; D015202:Protein Engineering; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D051844:alpha-Synuclein