Strange Richard W, Antonyuk Svetlana V, Hough Michael A, Doucette Peter A, Valentine Joan Selverstone, Hasnain S Samar
Molecular Biophysics Group, CCLRC Daresbury Laboratory, Warrington, Cheshire WA4 4AD, UK.
J Mol Biol. 2006 Mar 10;356(5):1152-62. doi: 10.1016/j.jmb.2005.11.081. Epub 2005 Dec 12.
Human Cu-Zn superoxide dismutase (SOD1) protects cells from the effects of oxidative stress. Mutations in SOD1 are linked to the familial form of amyotrophic lateral sclerosis. Several hypotheses for their toxicity involve the mis-metallation of the enzyme. We present atomic-resolution crystal structures and biophysical data for human SOD1 in three metallation states: Zn-Zn, Cu-Zn and as-isolated. These data represent the first atomic-resolution structures for human SOD1, the first structure of a reduced SOD1, and the first structure of a fully Zn-substituted SOD1 enzyme. Recombinantly expressed as-isolated SOD1 contains a mixture of Zn and Cu at the Cu-binding site. The Zn-Zn structure appears to be at least as stable as the correctly (Cu-Zn) metallated enzyme. These data raise the possibility that in a cellular environment with low availability of free copper, Zn-Zn may be the preferred metallation state of SOD1 prior to its interaction with the copper chaperone.
人类铜锌超氧化物歧化酶（SOD1）可保护细胞免受氧化应激的影响。SOD1突变与家族性肌萎缩侧索硬化症有关。关于其毒性的几种假说涉及该酶的错误金属化。我们展示了处于三种金属化状态的人类SOD1的原子分辨率晶体结构和生物物理数据：锌-锌、铜-锌和原样状态。这些数据代表了人类SOD1的首个原子分辨率结构、还原型SOD1的首个结构以及完全被锌取代的SOD1酶的首个结构。重组表达的原样状态的SOD1在铜结合位点含有锌和铜的混合物。锌-锌结构似乎至少与正确（铜-锌）金属化的酶一样稳定。这些数据增加了这样一种可能性，即在游离铜可用性低的细胞环境中，锌-锌可能是SOD1在与铜伴侣相互作用之前的首选金属化状态。
