Simulation of pH-dependent edge strand rearrangement in human beta-2 microglobulin.
Simulation of pH-dependent edge strand rearrangement in human beta-2 microglobulin.
复制标题
模拟人 β-2 微球蛋白中 pH 依赖性边缘链重排。
DOI：
10.1110/ps.051814306
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Saven,JefferyG
中科院分区：
文献类型：
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作者：
Park,Sheldon;Saven,JefferyG
由不相关蛋白质形成的淀粉样纤维通常具有形态学相似性，提示淀粉样蛋白形成的共同生物病理学机制。对人β 2微球蛋白（β 2 M）的生化研究表明，低pH值可以触发其从水溶性蛋白质向不溶性聚集体的转变。此外，使用NMR对β 2 M进行的生物物理测量已经确定了参与淀粉样蛋白原纤维形成的蛋白质残基。在pH 5.7下测定的单体人β 2 M的晶体结构显示，其边缘β链之一（链D）采用了与在较高pH下获得的相同蛋白质的其他结构不同的构象。这种交替的β链排列缺乏β凸起，这可能通过分子间β折叠缔合促进蛋白质聚集。为了探索pH变化是否会产生所观察到的构象差异，对β 2 M进行了分子动力学模拟。通过指定Asp、Glu和His的质子化状态以及主链的C末端来模拟pH的影响。在中等pH（pH 5-7）下优选链D的凸出构象，而在低pH（pH < 4）下观察到直链构象。因此，低pH可稳定边缘链D的直链构象，从而增加β 2 M的淀粉样蛋白生成。
Amyloid fibrils formed from unrelated proteins often share morphological similarities, suggesting common biophysicalmechanisms for amyloidogenesis. Biochemical studies of human β‐2 microglobulin (β2M) have shown that its transition from a water‐soluble protein to insoluble aggregates can be triggered by low pH. Additionally, biophysical measurements of β2M using NMR have identified residues of the protein that participate in the formation of amyloid fibrils. The crystal structure of monomeric human β2M determined at pH 5.7 shows that one of its edge β‐strands (strand D) adopts a conformation that differs from other structures of the same protein obtained at higher pH. This alternate β‐strand arrangement lacks a β‐bulge, which may facilitate protein aggregation through intermolecular β‐sheet association. To explore whether the pH change may yield the observed conformational difference, molecular dynamics simulations of β2M were performed. The effects of pH were modeled by specifying the protonation states of Asp, Glu, and His, as well as the C terminus of the main chain. The bulged conformation of strand D is preferred at medium pH (pH 5–7), whereas at low pH (pH < 4) the straight conformation is observed. Therefore, low pH may stabilize the straight conformation of edge strand D and thus increase the amyloidogenicity of β2M.