Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
J Am Chem Soc. 2010 Sep 29;132(38):13495-504. doi: 10.1021/ja1057136.
How coordination of metal ions modulates protein structures is not only important for elucidating biological function but has also emerged as a key determinant in protein turnover and protein-misfolding diseases. In this study, we show that the coordination of Zn(2+) to the ALS-associated enzyme Cu/Zn superoxide dismutase (SOD1) is directly controlled by the protein's folding pathway. Zn(2+) first catalyzes the folding reaction by coordinating transiently to the Cu ligands of SOD1, which are all contained within the folding nucleus. Then, after the global folding transition has commenced, the Zn(2+) ion transfers to the higher affinity Zn site, which structures only very late in the folding process. Here it remains dynamically coordinated with an off rate of ∼10(-5) s(-1). This relatively rapid equilibration of metals in and out of the SOD1 structure provides a simple explanation for how the exceptionally long lifetime, >100 years, of holoSOD1 is still compatible with cellular turnover: if a dissociated Zn(2+) ion is prevented from rebinding to the SOD1 structure then the lifetime of the protein is reduced to a just a few hours.
金属离子的协调如何调节蛋白质结构不仅对阐明生物学功能很重要，而且也是蛋白质周转和蛋白质错误折叠疾病的关键决定因素。在这项研究中，我们表明，与 ALS 相关的酶铜/锌超氧化物歧化酶（SOD1）中 Zn(2+)的配位直接受蛋白质折叠途径的控制。Zn(2+)首先通过暂时与 SOD1 的 Cu 配体配位来催化折叠反应，而这些 Cu 配体都包含在折叠核内。然后，在全局折叠转变开始后，Zn(2+)离子转移到具有更高亲和力的 Zn 结合位点，该位点仅在折叠过程的很晚阶段形成。在这里，它与约 10(-5) s(-1)的离解速率保持动态配位。这种金属在 SOD1 结构内外的快速平衡为解释完整 SOD1 的异常长寿命（>100 年）如何仍与细胞周转兼容提供了一个简单的解释：如果阻止解离的 Zn(2+)离子重新结合到 SOD1 结构中，则蛋白质的寿命会缩短到只有几个小时。
