Critical balance of electrostatic and hydrophobic interactions is required for β2-microglobulin amyloid fibril growth and stability
Critical balance of electrostatic and hydrophobic interactions is required for β2-microglobulin amyloid fibril growth and stability
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DOI：
10.1021/bi048029t
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发表时间：
2005-02-01
期刊：
影响因子：
2.9
通讯作者：
Goto, Y
中科院分区：
文献类型：
--
作者：
Raman, B;Chatani, E;Goto, Y
研究调节淀粉样蛋白形成的因素对理解和减轻淀粉样蛋白相关疾病很重要。为了了解静电相互作用和离子溶质（尤其是阴离子）对淀粉样蛋白形成的影响，我们研究了NaCl、NaI、NaClO4和Na2SO4等盐对o -2微球蛋白（参与透析相关淀粉样变性的蛋白质）淀粉样蛋白纤维生长的影响。在酸性条件下，这些盐表现出有利于纤维生长的特征最佳浓度。正如8-苯胺萘-1-磺酸所报道的那样，盐的存在导致蛋白质疏水性的增加，这表明阴离子相互作用导致了淀粉样蛋白形成所必需的静电和疏水平衡。然而，高浓度的盐使平衡倾向于高疏水性，导致蛋白质分裂成无定形聚集体。这种无定形的聚集体不适于纤维生长。从有利于淀粉样蛋白纤维形成的最低浓度来看，阴离子的排列顺序为SO42- > ClO4- > I- > Cl-，这与它们的电选择性序列顺序一致，说明在淀粉样蛋白纤维生长过程中，阴离子的优先结合而不是一般的离子强度效应起着重要作用。阴离子结合也被发现在酸性条件下稳定淀粉样蛋白原纤维。有趣的是，硫酸盐促进β(2)-微球蛋白的淀粉样蛋白生长在pH值在5和6之间，更接近它的等电点。考虑到早期关于糖胺聚糖和蛋白聚糖（即硫酸多阴离子）在淀粉样蛋白形成中的作用的研究，我们的研究表明硫酸盐离子与淀粉样蛋白的优先相互作用可能具有生物学意义。
Investigation of factors that modulate amyloid formation of proteins is important to understand and mitigate amyloid-related diseases. To understand the role of electrostatic interactions and the effect of ionic cosolutes, especially anions, on amyloid formation, we have investigated the effect of salts such as NaCl, NaI, NaClO4, and Na2SO4 on the amyloid fibril growth of O-2-microglobulin, the protein involved in dialysis-related amyloidosis. Under acidic conditions, these salts exhibit characteristic optimal concentrations where the fibril growth is favored. The presence of salts leads to an increase in hydrophobicity of the protein as reported by 8-anilinonaphthalene-1-sulfonic acid, indicating that the anion interaction leads to the necessary electrostatic and hydrophobic balance critical for amyloid formation. However, high concentrations of salts tilt the balance to high hydrophobicity, leading to partitioning of the protein to amorphous aggregates. Such amorphous aggregates are not competent for fibril growth. The order of anions based on the lowest concentration at which fibril formation is favored is SO42- > ClO4- > I- > Cl-, consistent with the order of their electroselectivity series, suggesting that preferential anion binding, rather than general ionic strength effect, plays an important role in the amyloid fibril growth. Anion binding is also found to stabilize the amyloid fibrils under acidic condition. Interestingly, sulfate promotes amyloid growth of beta(2)-microglobulin at pH between 5 and 6, closer to its isoelectric point. Considering the earlier studies on the role of glycosaminoglycans and proteoglycans (i.e., sulfated polyanions) on amyloid formation, our study suggests that preferential interaction of sulfate ions with amyloidogenic proteins may have biological significance.