Nookala Ravi K, Hussain Shobbir, Pellegrini Luca
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1GA, UK.
Nucleic Acids Res. 2007;35(5):1638-48. doi: 10.1093/nar/gkm033. Epub 2007 Feb 18.
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.
范可尼贫血（FA）是一种癌症易感性疾病，其特征是自发染色体断裂以及细胞对基因毒性剂高度敏感。响应DNA损伤时，FA蛋白的多亚基组装体即FA核心复合物会将下游的FANCD2蛋白单泛素化。FANCE蛋白作为FA核心复合物中与FANCD2结合的组分，在FA的DNA修复过程中发挥着至关重要的作用。在此，我们报告了对人类FANCE的晶体学和生物学研究。一种FA蛋白的首个结构揭示了存在一个重复的螺旋基序，该基序为范可尼贫血中其他缺陷蛋白的结构合理化提供了模板。我们通过晶体学分析确定的FANCE部分足以与FANCD2相互作用，从而为FANCD2募集到FA核心复合物的模式提供了结构信息。与疾病相关的突变破坏了FANCE-FANCD2相互作用，为FA发病机制的分子机制提供了结构上的见解。
