The coupling between disulphide status, metallation and dimer interface strength in Cu/Zn superoxide dismutase
The coupling between disulphide status, metallation and dimer interface strength in Cu/Zn superoxide dismutase
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DOI：
10.1016/j.jmb.2006.09.048
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发表时间：
2007-01-12
影响因子：
5.6
通讯作者：
Oliveberg, Mikael
中科院分区：
文献类型：
--
作者：
Hornberg, Andreas;Logan, Derek T.;Oliveberg, Mikael
肌萎缩侧索硬化症（ALS）中神经毒性功能的获得与同二聚体酶Cu/Zn超氧化物歧化酶（SOD）的错误折叠有关。在这里，我们提出了完全半胱氨酸耗尽的人SOD（SOD（CallA））的晶体结构，在体内的折叠途径，也被牵连为神经毒性前体状态，代表减少，边缘稳定的中间体。该物种的一个特点是，它不能二聚化，并在缺乏活性位点金属的情况下被捕获为单体。晶体学数据表明，C57-C146二硫键的去除释放了载脂蛋白中的界面环IV，而相同的环在全蛋白中保持不受影响。因此，二硫化物还原的apoSOD的低二聚化倾向似乎是熵的起源，由于在单体状态下的环的灵活性增加：在二硫化物还原的holo蛋白质中，这种增益在二聚体界面分裂时的构型熵减少了金属配位。(c)2006爱思唯尔有限公司保留所有权利。
The gain of neurotoxic function in amyotrophic lateral sclerosis (ALS) has been linked to misfolding of the homodimeric enzyme Cu/Zn superoxide dismutase (SOD). Here, we present the crystal structure of fully cysteine-depleted human SOD (SOD (CallA)), representing a reduced, marginally stable intermediate on the folding pathway in vivo that has also been implicated as neurotoxic precursor state. A hallmark of this species is that it fails to dimerise and becomes trapped as a monomer in the absence of the active-site metals. The crystallographic data show that removal of the C57-C146 disulphide bond sets free the interface loop IV in the apo protein, whereas the same loop remains unaffected in the holo protein. Thus, the low dimerisation propensity of disulphide-reduced apoSOD seems to be of entropic origin due to increased loop flexibility in the monomeric state: in the disulphide-reduced holo protein this gain in configurational entropy upon splitting of the dimer interface is reduced by the metal coordination. (c) 2006 Elsevier Ltd. All rights reserved.