The E46K mutation in α-synuclein increases amyloid fibril formation
The E46K mutation in α-synuclein increases amyloid fibril formation
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DOI：
10.1074/jbc.m411638200
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发表时间：
2005-03-04
影响因子：
4.8
通讯作者：
Giasson, BI
中科院分区：
文献类型：
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作者：
Greenbaum, EA;Graves, CL;Giasson, BI
在α-突触核蛋白的氨基末端区域的KTKEGV型重复序列之一中鉴定到新的突变（E46 K）表明，该区域，更具体地说，重复序列中的Glu残基可能在调节α-突触核蛋白转录成淀粉样原纤维的能力中是重要的。结果表明，E46 K突变增加了α-突触核蛋白的fifluze倾向，但这种影响小于A53 T突变。Glu（46）取代Ala也增加了α-突触核蛋白的组装，但形成的聚合物可以具有不同的超微结构，进一步表明该氨基酸位置对组装过程具有显著影响。还研究了α-突触核蛋白的第六重复序列中残基Glu（83）的影响，该重复序列最接近细丝组装的关键氨基酸拉伸。Glu（83）突变为Lys或Ala增加了聚合，但扰乱了成熟淀粉样蛋白的某些特性。这些结果表明，重复序列中的一些Glu残基可以对调节α-突触核蛋白的组装以形成淀粉样纤维产生显着影响。A53 T突变的更大影响，即使与可能预测为更显著的突变（如E46 K）相比，也强调了蛋白质微环境在影响蛋白质结构方面的重要性。此外，A53 T和E46 K突变的相对影响与疾病发作的年龄一致。这些发现支持了导致病理性包涵体形成的异常α-突触核蛋白聚合可导致疾病的观点。
The identification of a novel mutation (E46K) in one of the KTKEGV-type repeats in the amino-terminal region of alpha-synuclein suggests that this region and, more specifically, Glu residues in the repeats may be important in regulating the ability of alpha-synuclein to polymerize into amyloid fibrils. It was demonstrated that the E46K mutation increased the propensity of alpha-synuclein to fibrillize, but this effect was less than that of the A53T mutation. The substitution of Glu(46) for an Ala also increased the assembly of alpha-synuclein, but the polymers formed can have different ultrastructures, further indicating that this amino acid position has a significant effect on the assembly process. The effect of residue Glu(83) in the sixth repeat of alpha-synuclein, which lies closest to the amino acid stretch critical for filament assembly, was also studied. Mutation of Glu(83) to a Lys or Ala increased polymerization but perturbed some of the properties of mature amyloid. These results demonstrated that some of the Glu residues within the repeats can have significant effects on modulating the assembly of alpha-synuclein to form amyloid fibrils. The greater effect of the A53T mutation, even when compared with what may be predicted to be a more dramatic mutation such as E46K, underscores the importance of protein micro-environment in affecting protein structure. Moreover, the relative effects of the A53T and E46K mutations are consistent with the age of onset of disease. These findings support the notion that aberrant alpha-synuclein polymerization resulting in the formation of pathological inclusions can lead to disease.