Glover J N Mark
Department of Biochemistry, University of Alberta, T6G 2H7, Edmonton, AB, Canada.
Fam Cancer. 2006;5(1):89-93. doi: 10.1007/s10689-005-2579-z.
The C-terminal, BRCT repeats of BRCA1 are essential for the tumor suppressor function of this protein. Here we review structural and functional studies of this domain. Both repeats adopt similar folds and pack in an intimate, head-to-tail manner. The domain binds phosphorylated targets such as the DNA damage-associated kinase BACH1, with a specificity for pSer-X-X-Phe motifs. Structural studies reveal that the N-terminal repeat is responsible for pSer binding while a groove at the interface of the two repeats recognizes the Phe. Missense variants identified in breast cancer screening programs often disrupt these interactions and these molecular defects may lead to an increased cancer risk.
BRCA1蛋白的C末端BRCT重复序列对于该蛋白的肿瘤抑制功能至关重要。在此，我们综述了对该结构域的结构和功能研究。两个重复序列具有相似的折叠方式，并以紧密的头对头方式堆积。该结构域结合磷酸化靶标，如与DNA损伤相关的激酶BACH1，对pSer-X-X-Phe基序具有特异性。结构研究表明，N末端重复序列负责结合pSer，而两个重复序列界面处的一个凹槽识别Phe。在乳腺癌筛查项目中鉴定出的错义变体常常破坏这些相互作用，这些分子缺陷可能导致癌症风险增加。
