期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 389, 期 2, 页码 413-424出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2009.03.021
关键词
alpha-synuclein; Parkinson's disease; secondary structure; N-terminus; yeast toxicity
资金
- Morris K. Udall Parkinson's Disease Research Center of Excellence [NS038375]
- Swiss National Science Foundation
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.
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