The 1.1-Å resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease
The 1.1-Å resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease
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DOI：
10.1073/pnas.1133288100
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发表时间：
2003-08-05
影响因子：
11.1
通讯作者：
Petsko, GA
中科院分区：
文献类型：
--
作者：
Wilson, MA;Collins, JL;Petsko, GA
DJ-1是一种在所有生命界的生物体中具有同源物的人类基因，其突变已被证明与常染色体隐性遗传的早发性帕金森病（PARK 7）相关。我们在这里报告的三维结构的DJ-1蛋白质，确定在1.1埃的分辨率通过X射线晶体学。DJ-1的链折叠类似于已被注释为半胱氨酸蛋白酶的细菌蛋白Pfpl的链折叠，以及细菌过氧化氢酶的结构域的链折叠，所述过氧化氢酶的结构域在该酶的活性中的作用是不确定的。Pfpl是一种六聚体蛋白，其寡聚体结构对其推定的蛋白水解活性至关重要，而DJ-1是一种具有完全不同亚基间接触的二聚体。建议的催化三联体的PfpI是从相应的区域的DJ-1的结构是不存在的，和生化测定未能检测到任何蛋白酶活性纯化的DJ-1。一个高度保守的半胱氨酸残基，这是在DJ-1的同源物中催化必需的，显示出对辐射损伤的极端敏感性，并且也可能受到其他形式的氧化修饰。该结构表明，DJ-1中帕金森病相关突变L166 P引起的功能丧失是由于二聚体界面的不稳定。总之，人DJ-1的晶体结构加上其他观察结果表明，这种蛋白质可能参与细胞氧化应激反应和神经退行性疾病的一般病因。
Mutations in DJ-1, a human gene with homologues in organisms from all kingdoms of life, have been shown to be associated with autosomal recessive, early onset Parkinson's disease (PARK7). We report here the three-dimensional structure of the DJ-1 protein, determined at a resolution of 1.1 Angstrom by x-ray crystallography. The chain fold of DJ-1 resembles those of a bacterial protein, Pfpl, that has been annotated as a cysteine protease, and of a domain of a bacterial catalase whose role in the activity of that enzyme is uncertain. In contrast to Pfpl, a hexameric protein whose oligomeric structure is essential for its putative proteolytic activity, DJ-1 is a dimer with completely different intersubunit contacts. The proposed catalytic triad of PfpI is absent from the corresponding region of the structure of DJ-1, and biochemical assays fail to detect any protease activity for purified DJ-1. A highly conserved cysteine residue, which is catalytically essential in homologues of DJ-1, shows an extreme sensitivity to radiation damage and may be subject to other forms of oxidative modification as well. The structure suggests that the loss of function caused by the Parkinson's-associated mutation L166P in DJ-1 is due to destabilization of the dimer interface. Taken together, the crystal structure of human DJ-1 plus other observations suggest the possible involvement of this protein in the cellular oxidative stress response and a general etiology of neurodegenerative diseases.