A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly

被引:822
|
作者
Giasson, BI [1 ]
Murray, IVJ [1 ]
Trojanowski, JQ [1 ]
Lee, VMY [1 ]
机构
[1] Univ Penn, Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
关键词
D O I
10.1074/jbc.M008919200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neuronal and oligodendrocytic aggregates of fibrillar alpha -synuclein define several diseases of the nervous system. It is likely that these inclusions impair vital metabolic processes and compromise vialibity of affected cells. Here, we report that a 12-amino acid stretch ((71)VTGVTAVAQKTV(82)) in the middle of the hydrophobic domain of human alpha -synuclein is necessary and sufficient for its fibrillization based on the following observations: 1) human beta -synuclein is highly homologous to alpha -synuclein but lacks these 12 residues, and it does not assemble into filaments in vitro; 2) the rate of alpha -synuclein polymerization in vitro decreases after the introduction of a single charged amino acid within these 12 residues, and a deletion within this region abrogates assembly; 3) this stretch of 12 amino acids appears to form the core of alpha -synuclein filaments, because it is resistant to proteolytic digestion in alpha -synuclein filaments; and 4) synthetic peptides corresponding to this 12-amino acid stretch self-polymerize to form filaments, and these peptides promote fibrillization of full-length human alpha -synuclein in vitro. Thus, we have identified key sequence elements necessary for the assembly of human alpha -synuclein into filaments, and these elements may be exploited as targets for the design of drugs that inhibit alpha -synuclein fibrillization and might arrest disease progression.
引用
收藏
页码:2380 / 2386
页数:7
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