Cu(II) organizes β-2-microglobulin oligomers but is released upon amyloid formation
Cu(II) organizes β-2-microglobulin oligomers but is released upon amyloid formation
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DOI：
10.1110/ps.073249008
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发表时间：
2008-04-01
期刊：
影响因子：
8
通讯作者：
Vachet, Richard W.
中科院分区：
文献类型：
--
作者：
Antwi, Kwasi;Mahar, Maura;Vachet, Richard W.
β -2微球蛋白（β 2m）以淀粉样原纤维的形式沉积在因肾衰竭而接受长期透析治疗的患者的骨骼和关节中。先前的研究表明，在体外生理条件下，生物学上相关量的Cu（II）可以导致β 2m转化为淀粉样原纤维。在这项工作中，动态光散射、质谱和尺寸排除色谱被用来表征Cu在纤维形成之前的低聚中间体形成中的作用。Cu（II）对于二聚体的稳定性和四聚体的初始形式是必需的。最初形成的四聚体在进入六聚体状态之前经历结构变化，不再与Cu（II）结合。基于这些结果，我们提出与β 2m纤维形成相关的滞后期部分是由导致Cu（II）损失的四聚体的结构转变引起的。与这一观察一致的是确定成熟的β 2m淀粉样蛋白原纤维不含铜。因此，Cu（II）似乎通过在β 2m淀粉样蛋白形成之前组织必要的低聚中间体发挥催化作用。
beta-2-Microglobulin (beta 2m) is deposited as amyloid fibrils in the bones and joints of patients undergoing long-term dialysis treatment as a result of kidney failure. Previous work has shown that biologically relevant amounts of Cu(II) can cause beta 2m to be converted to amyloid fibrils under physiological conditions in vitro. In this work, dynamic light scattering, mass spectrometry, and size-exclusion chromatography are used to characterize the role that Cu plays in the formation of oligomeric intermediates that precede fibril formation. Cu( II) is found to be necessary for the stability of the dimer and an initial form of the tetramer. The initially formed tetramer then undergoes a structural change to a state that no longer binds Cu( II) before progressing to a hexameric state. Based on these results, we propose that the lag phase associated with beta 2m fibril formation is partially accounted for by the structural transition of the tetramer that results in Cu( II) loss. Consistent with this observation is the determination that the mature beta 2m amyloid fibrils do not contain Cu. Thus, Cu( II) appears to play a catalytic role by enabling the organization of the necessary oligomeric intermediates that precede beta 2m amyloid formation.