Insights into Fanconi Anaemia from the structure of human FANCE
Insights into Fanconi Anaemia from the structure of human FANCE
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DOI：
10.1093/nar/gkm033
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发表时间：
2007-01-01
影响因子：
14.9
通讯作者：
Pellegrini, Luca
中科院分区：
文献类型：
--
作者：
Nookala, Ravi K.;Hussain, Shobbir;Pellegrini, Luca
范可尼贫血（FA）是一种癌症易感性疾病，其特征是自发性染色体断裂和细胞对遗传毒性物质的高度敏感性。为了响应DNA损伤，FA蛋白质的多亚基组装体，FA核心复合物，单泛素化下游FANCD 2蛋白。FANCE蛋白作为FA核心复合物的FANCD 2结合组分，在DNA修复的FA过程中发挥重要作用。在这里，我们报告了人类FANCE的晶体学和生物学研究。FA蛋白的第一个结构揭示了重复螺旋基序的存在，为范可尼贫血中其他蛋白质缺陷的结构合理化提供了模板。通过我们的晶体学分析定义的FANCE部分足以与FANCD 2相互作用，产生FANCD 2募集至FA核心复合物的模式的结构信息。疾病相关突变破坏FANCE-FANCD 2相互作用，为FA发病机制的分子机制提供结构性见解。
Fanconi Anaemia (FA) is a cancer predisposition disorder characterized by spontaneous chromosome breakage and high cellular sensitivity to genotoxic agents. In response to DNA damage, a multi-subunit assembly of FA proteins, the FA core complex, monoubiquitinates the downstream FANCD2 protein. The FANCE protein plays an essential role in the FA process of DNA repair as the FANCD2-binding component of the FA core complex. Here we report a crystallographic and biological study of human FANCE. The first structure of a FA protein reveals the presence of a repeated helical motif that provides a template for the structural rationalization of other proteins defective in Fanconi Anaemia. The portion of FANCE defined by our crystallographic analysis is sufficient for interaction with FANCD2, yielding structural information into the mode of FANCD2 recruitment to the FA core complex. Disease-associated mutations disrupt the FANCE-FANCD2 interaction, providing structural insight into the molecular mechanisms of FA pathogenesis.