Assessing the role of aromatic residues in the amyloid aggregation of human muscle acylphosphatase
Assessing the role of aromatic residues in the amyloid aggregation of human muscle acylphosphatase
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DOI：
10.1110/ps.051915806
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发表时间：
2006-04-01
期刊：
影响因子：
8
通讯作者：
Chiti, F
中科院分区：
文献类型：
--
作者：
Bemporad, F;Taddei, N;Chiti, F
在已经提出的促进淀粉样蛋白原纤维形成的许多参数中，芳香残基的π堆积是其中之一。我们研究了几种人肌肉酰基磷酸酶突变体的淀粉样蛋白聚集，其中芳香残基被非芳香残基取代。使用硫磺素T测试在其中变体最初占据部分未折叠构象的集合的条件下测定聚集速率。序列的促进聚集片段中的取代导致蛋白质的聚集速率显著降低，证实了芳香族残基促进该过程的倾向。然而，统计分析表明，突变后测量到的聚集率降低主要是由于疏水性和固有β-折叠倾向的降低。这表明芳香族残基有利于聚集，因为这些因素，而不是他们的芳香性。
Among the many parameters that have been proposed to promote amyloid fibril formation is the pi-stacking of aromatic residues. We have studied the amyloid aggregation of several mutants of human muscle acylphosphatase in which an aromatic residue was substituted with a non-aromatic one. The aggregation rate was determined using the Thioflavin T test under conditions in which the variants populated initially an ensemble of partially unfolded conformations. Substitutions in aggregation-promoting fragments of the sequence result in a dramatically decreased aggregation rate of the protein, confirming the propensity of aromatic residues to promote this process. Nevertheless, a statistical analysis shows that the measured decrease of aggregation rate following mutation arises predominantly from a reduction of hydrophobicity and intrinsic beta-sheet propensity. This suggests that aromatic residues favor aggregation because of these factors rather than for their aromaticity.