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J Mol Biol. 2009 Jun 5;389(2):413-24. doi: 10.1016/j.jmb.2009.03.021. Epub 2009 Mar 13.

The first N-terminal amino acids of alpha-synuclein are essential for alpha-helical structure formation in vitro and membrane binding in yeast.

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  • 1Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.


Alpha-synuclein (alpha-syn), a protein implicated in Parkinson's disease, is structurally diverse. In addition to its random-coil state, alpha-syn can adopt an alpha-helical structure upon lipid membrane binding or a beta-sheet structure upon aggregation. We used yeast biology and in vitro biochemistry to detect how sequence changes alter the structural propensity of alpha-syn. The N-terminus of the protein, which adopts an alpha-helical conformation upon lipid binding, is essential for membrane binding in yeast, and variants that are more prone to forming an alpha-helical structure in vitro are generally more toxic to yeast. beta-Sheet structure and inclusion formation, on the other hand, appear to be protective, possibly by sequestering the protein from the membrane. Surprisingly, sequential deletion of residues 2 through 11 caused a dramatic drop in alpha-helical propensity, vesicle binding in vitro, and membrane binding and toxicity in yeast, part of which could be mimicked by mutating aspartic acid at position 2 to alanine. Variants with distinct structural preferences, identified here by a reductionist approach, provide valuable tools for elucidating the nature of toxic forms of alpha-syn in neurons.

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