Monoubiquitination of the Fanconi anemia complementation group D2 (FANCD2) protein by the FA core ubiquitin ligase complex is the central event in the FA pathway. FANCA and FANCG play major roles in the nuclear localization of the FA core complex. Mutations of these two genes are the most frequently observed genetic alterations in FA patients, and most point mutations in FANCA are clustered in the C-terminal domain (CTD). To understand the basis of the FA-associated FANCA mutations, we determined the cryo-electron microscopy (EM) structures of Xenopus laevis FANCA alone at 3.35 Å and 3.46 Å resolution and two distinct FANCA-FANCG complexes at 4.59 and 4.84 Å resolution, respectively. The FANCA CTD adopts an arc-shaped solenoid structure that forms a pseudo-symmetric dimer through its outer surface. FA- and cancer-associated point mutations are widely distributed over the CTD. The two different complex structures capture independent interactions of FANCG with either FANCA C-terminal HEAT repeats, or the N-terminal region. We show that mutations that disturb either of these two interactions prevent the nuclear localization of FANCA, thereby leading to an FA pathway defect. The structure provides insights into the function of FANCA CTD, and provides a framework for understanding FA- and cancer-associated mutations.

中文翻译：

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FANCA和FANCG复合物中范可尼贫血相关突变的结构基础。

FA核心泛素连接酶复合物对Fanconi贫血补充组D2（FANCD2）蛋白的单泛素化是FA途径中的中心事件。FANCA和FANCG在FA核心复合体的核定位中起着重要作用。这两个基因的突变是FA患者中最常观察到的遗传突变，并且FANCA中的大多数点突变都聚集在C末端域（CTD）中。为了了解与FA相关的FANCA突变的基础，我们确定了非洲爪蟾FANCA单独的冷冻电子显微镜（EM）结构，其分辨率分别为3.35Å和3.46Å，以及两种分别为4.59和4.84Å分辨率的FANCA-FANCG复合物。 。FANCA CTD采用弧形螺线管结构，该螺线管结构通过其外表面形成伪对称的二聚体。FA和癌症相关的点突变广泛分布在CTD上。两种不同的复杂结构捕获FANCG与FANCA C末端HEAT重复序列或N末端区域的独立相互作用。我们表明，干扰这两个相互作用中的任何一个的突变阻止了FANCA的核定位，从而导致了FA途径的缺陷。该结构为FANCA CTD的功能提供了见识，并为理解FA和癌症相关的突变提供了框架。