Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the γ-H2AX histone tail
Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the γ-H2AX histone tail
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DOI：
10.1074/jbc.c500273200
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发表时间：
2005-09-16
影响因子：
4.8
通讯作者：
Glover, JNM
中科院分区：
文献类型：
--
作者：
Lee, MS;Edwards, RA;Glover, JNM
MDC1 （DNA损伤检查点蛋白1的介质）通过与含有组蛋白变体H2AX的cooh末端磷酸化形式的核灶相互作用，调节哺乳动物细胞中DNA双链断裂的识别和修复。在这里，我们证明了MDC1的串联BRCT重复序列直接结合到H2AX-Ser(P)-Gln-Glu-Tyr的磷酸化尾部，以一种严重依赖于cooh末端Tyr残基的游离羧酸基的方式。我们以1.45埃的分辨率确定了MDC1 BRCT重复序列的x射线晶体结构。通过与与磷酸肽结合的BRCA1 BRCT的结构进行比较，我们认为MDC1中的两个精氨酸残基Arg（1932）和Arg（1933）可能识别肽的COOH末端以及H2AX的第二个Glu，而Gln（2013）可能为COOH末端Tyr提供额外的特异性。
MDC1 ( mediator of DNA damage checkpoint protein 1) regulates the recognition and repair of DNA double strand breaks in mammalian cells through its interactions with nuclear foci containing the COOH-terminally phosphorylated form of the histone variant, H2AX. Here we demonstrate that the tandem BRCT repeats of MDC1 directly bind to the phosphorylated tail of H2AX-Ser(P)-Gln-Glu-Tyr, in a manner that is critically dependent on the free carboxylate group of the COOH-terminal Tyr residue. We have determined the x-ray crystal structure of the MDC1 BRCT repeats at 1.45 angstrom resolution. By a comparison with the structure of the BRCA1 BRCT bound to a phosphopeptide, we suggest that two arginine residues in MDC1, Arg(1932) and Arg(1933) may recognize the COOH terminus of the peptide as well as the penultimate Glu of H2AX, while Gln(2013) may provide additional specificity for the COOH-terminal Tyr.