The First N-terminal Amino Acids of α-Synuclein Are Essential for α-Helical Structure Formation In Vitro and Membrane Binding in Yeast

JOURNAL OF MOLECULAR BIOLOGY

卷:389

Article

Lansbury, Peter T., Jr.¹ 

[1] Harvard Univ, Ctr Neurol Dis, Brigham & Womens Hosp, Sch Med, Cambridge, MA 02139 USA

关键词: alpha-synuclein;    Parkinson's disease;    secondary structure;    N-terminus;    yeast toxicity;   

DOI  :  10.1016/j.jmb.2009.03.021

来源: Elsevier

【 摘 要 】

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. (C) 2009 Published by Elsevier Ltd.

【 授权许可】

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