Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer
Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer
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DOI：
10.1038/nsmb775
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发表时间：
2004-06-01
影响因子：
16.8
通讯作者：
Smerdon, SJ
中科院分区：
文献类型：
--
作者：
Clapperton, JA;Manke, IA;Smerdon, SJ
BRCA1抑癌基因的胚系突变通常会导致乳腺癌和卵巢癌的易感性显著增加。尽管它们的作用的分子基础在很大程度上仍然不清楚，但已知许多突变针对高度保守的C-末端BRCT重复序列，该重复序列起着磷酸丝氨酸/磷酸苏氨酸结合模块的作用。我们报道了分辨率为1.85的BRCA1串联BRCT结构域的X射线晶体结构，其中一个磷酸化肽代表Deah-box解旋酶BACH1的最小相互作用区域。该结构揭示了这类新的BRCA1结合事件的决定因素。我们证明了与疾病相关的突变的子集是通过磷酸依赖的BRCA1相互作用的特定破坏而不是通过串联BRCT结构域的总体结构扰动来发挥作用的。
Germline mutations in the BRCA1 tumor suppressor gene often result in a significant increase in susceptibility to breast and ovarian cancers. Although the molecular basis of their effects remains largely obscure, many mutations are known to target the highly conserved C-terminal BRCT repeats that function as a phosphoserine/phosphothreonine-binding module. We report the X-ray crystal structure at a resolution of 1.85 of the BRCA1 tandem BRCT domains in complex with a phosphorylated peptide representing the minimal interacting region of the DEAH-box helicase BACH1. The structure reveals the determinants of this novel class of BRCA1 binding events. We show that a subset of disease-linked mutations act through specific disruption of phospho-dependent BRCA1 interactions rather than through gross structural perturbation of the tandem BRCT domains.