Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
Biochemistry. 2012 Oct 30;51(43):8478-90. doi: 10.1021/bi300574r. Epub 2012 Oct 16.
Amyloid formation plays a role in a wide range of human diseases. The rate and extent of amyloid formation depend on solution conditions, including pH and ionic strength. Amyloid fibrils often adopt structures with parallel, in-register β-sheets, which generate quasi-infinite arrays of aligned side chains. These arrangements can lead to significant electrostatic interactions between adjacent polypeptide chains. The effect of ionic strength and ion composition on the kinetics of amyloid formation by islet amyloid polypeptide (IAPP) is examined. IAPP is a basic 37-residue polypeptide responsible for islet amyloid formation in type 2 diabetes. Poisson-Boltzmann calculations revealed significant electrostatic repulsion in a model of the IAPP fibrillar state. The kinetics of IAPP amyloid formation are strongly dependent on ionic strength, varying by a factor of >10 over the range of 20-600 mM NaCl at pH 8.0, but the effect is not entirely due to Debye screening. At low ionic strengths, the rate depends strongly on the identity of the anion, varying by a factor of nearly 4, and scales with the electroselectivity series, implicating anion binding. At high ionic strengths, the rate varies by only 8% and scales with the Hofmeister series. At intermediate ionic strengths, no clear trend is detected, likely because of the convolution of different effects. The effects of salts on the growth phase and lag phase of IAPP amyloid formation are strongly correlated. At pH 5.5, where the net charge on IAPP is higher, the effect of different anions scales with the electroselectivity series at all salt concentrations.
淀粉样蛋白的形成在多种人类疾病中起着重要作用。淀粉样蛋白的形成速度和程度取决于溶液条件，包括 pH 值和离子强度。淀粉样纤维通常采用具有平行、对位β-折叠的结构，这些结构产生准无限排列的侧链。这些排列方式可以导致相邻多肽链之间产生显著的静电相互作用。本文研究了离子强度和离子组成对胰岛淀粉样多肽（IAPP）形成淀粉样蛋白的动力学的影响。IAPP 是一种碱性的 37 个氨基酸残基的多肽，负责 2 型糖尿病中的胰岛淀粉样形成。泊松-玻尔兹曼计算揭示了在 IAPP 纤维态模型中存在显著的静电排斥。IAPP 淀粉样蛋白形成的动力学强烈依赖于离子强度，在 pH8.0 时，20-600mM NaCl 范围内变化超过 10 倍，但这种影响并非完全归因于德拜屏蔽。在低离子强度下，速率强烈依赖于阴离子的种类，变化近 4 倍，并与电选择性序列一致，表明阴离子结合。在高离子强度下，速率仅变化 8%，并与霍夫迈斯特序列一致。在中间离子强度下，未检测到明显的趋势，可能是由于不同效应的卷积。盐对 IAPP 淀粉样蛋白形成的生长阶段和迟滞阶段的影响具有很强的相关性。在 pH5.5 下，IAPP 的净电荷较高，不同阴离子的影响与所有盐浓度下的电选择性序列一致。
