The clustering and spatial arrangement of beta-sheet sequence, but not order, govern alpha-synuclein fibrillogenesis.

ABSTRACT: The intrinsically unstructured protein alpha-synuclein (aS) is prone to misfold into cytotoxic beta-sheet-rich oligomers and amyloid fibrils that underlie the pathogenesis of Lewy body diseases such as Parkinson's disease. An important, recognized fibrillogenesis parameter is amino acid content, whereas the influence of amino acid sequence distribution is not as well understood. The fibril core of aS encompasses five regions of high beta-sheet propensity, termed beta1-beta5. Using four aS variants with identical amino acid compositions but rearranged pseudorepeat motifs, we show that beta2-beta5 sequence clustering, but not order, is important for efficient fibrillogenesis. For molecular species progressing toward the fibrillar state, order invariably increases; i.e., the spatial arrangeme

SUBMITTER: Suk JE 

PROVIDER: S-EPMC2841006 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature