Hörnberg Andreas, Logan Derek T, Marklund Stefan L, Oliveberg Mikael
Department of Biochemistry, Umeå University, SE-901 87 Umeå, Sweden.
J Mol Biol. 2007 Jan 12;365(2):333-42. doi: 10.1016/j.jmb.2006.09.048. Epub 2006 Sep 23.
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 dimerize 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.
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铜/锌超氧化物歧化酶（SOD）的错误折叠有关。在此，我们展示了完全缺失半胱氨酸的人SOD（SOD(CallA)）的晶体结构，它代表了体内折叠途径上一种还原的、稳定性略低的中间体，也被认为是神经毒性前体状态。该物种的一个标志是它无法二聚化，并且在没有活性位点金属的情况下会被困为单体。晶体学数据表明，去除C57-C146二硫键会使脱辅基蛋白中的界面环IV游离，而同一环在全酶蛋白中不受影响。因此，二硫键还原的脱辅基SOD的低二聚化倾向似乎源于熵增，这是由于单体状态下环的灵活性增加：在二硫键还原的全酶蛋白中，二聚体界面分裂时构象熵的增加会因金属配位而降低。
