Structure of an XRCC1 BRCT domain:: a new protein-protein interaction module
Structure of an XRCC1 BRCT domain:: a new protein-protein interaction module
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DOI：
10.1093/emboj/17.21.6404
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发表时间：
1998-11-02
期刊：
影响因子：
11.4
通讯作者：
Freemont, PS
中科院分区：
文献类型：
--
作者：
Zhang, XD;Moréra, S;Freemont, PS
BRCT结构域（BRCA1 C-terminus）首先在乳腺癌抑制蛋白BRCA1中被发现，是一个进化保守的蛋白-蛋白相互作用区域，类似于大量参与DNA修复、重组和细胞周期控制的蛋白质中的95个氨基酸。在这里，我们描述了用x射线晶体学在3.2埃分辨率下确定的BRCT结构域的第一个三维结构和折叠。该结构是从人类DNA修复蛋白XRCC1的c端区域获得的，包括一个由三个α螺旋包围的四链平行β片，形成一个自主折叠的结构域。紧凑的XRCC1结构解释了观察到的不同BRCT基序之间的序列同源性，并为其他BRCT结构域的建模提供了框架，此外，XRCC1的已建立结构。BRCT同二聚体提示了DNA连接酶III中互补BRCT结构域的潜在蛋白-蛋白相互作用位点，因为这两个结构域形成了稳定的异二聚体复合物。基于XRCC1 BRCT结构，我们构建了BRCA1的c端BRCT结构域模型，该结构域在家族性乳腺癌和卵巢癌中经常发生突变。该模型允许深入了解这些突变对BRCT结构域折叠的影响。
The BRCT domain (BRCA1 C-terminus), first identified in the breast cancer suppressor protein BRCA1, is an evolutionarily conserved protein-protein interaction region of similar to 95 amino acids found in a large number of proteins involved in DNA repair, recombination and cell cycle control, Here we describe the first three-dimensional structure and fold of a BRCT domain determined by X-ray crystallography at 3.2 Angstrom resolution. The structure has been obtained from the C-terminal region of the human DNA repair protein XRCC1, and comprises a four-stranded parallel beta-sheet surrounded by three alpha-helices, which form an autonomously folded domain. The compact XRCC1 structure explains the observed sequence homology between different BRCT motifs and provides a framework for modelling other BRCT domains, Furthermore, the established structure of an XRCC1. BRCT homodimer suggests potential protein-protein interaction sites for the complementary BRCT domain in DNA ligase III, since these two domains form a stable heterodimeric complex, Based on the XRCC1 BRCT structure, we have constructed a model for the C-terminal BRCT domain of BRCA1, which frequently is mutated in familial breast and ovarian cancer. The model allows insights into the effects of such mutations on the fold of the BRCT domain.