Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1.
Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1.
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DOI：
10.1126/science.1216338
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发表时间：
2012-05-11
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影响因子：
--
通讯作者：
Pascal JM
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文献类型：
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作者：
Langelier MF;Planck JL;Roy S;Pascal JM
聚 (ADP-核糖) 聚合酶-1 (PARP-1) 具有模块化结构域结构，可通过一种鲜为人知的机制将 DNA 损伤检测与聚 (ADP-核糖基) 化活性结合起来。在这里，我们报告了与激活所必需的人类 PARP-1 结构域（Zn1、Zn3、WGR-CAT）复合物中 DNA 双链断裂的晶体结构。 PARP-1 作为单体与 DNA 结合，与 DNA 损伤的相互作用将 PARP-1 结构域组织成折叠构象，这可以解释对自动修饰的强烈偏好。 Zn1、Zn3 和 WGR 结构域共同与 DNA 结合，形成将 DNA 损伤界面与催化结构域 (CAT) 连接起来的结构域间接触网络。 DNA 损伤诱导的 PARP-1 构象会导致结构扭曲，从而破坏 CAT 的稳定性。我们的结果表明 CAT 蛋白动力学的增加是 PARP-1 的 DNA 依赖性激活机制的基础。
Poly(ADP-ribose) polymerase-1 (PARP-1) has a modular domain architecture that couples DNA damage detection to poly(ADP-ribosyl)ation activity through a poorly understood mechanism. Here we report the crystal structure of a DNA double-strand break in complex with human PARP-1 domains essential for activation (Zn1, Zn3, WGR-CAT). PARP-1 engages DNA as a monomer, and the interaction with DNA damage organizes PARP-1 domains into a collapsed conformation that can explain the strong preference for automodification. The Zn1, Zn3, and WGR domains collectively bind to DNA, forming a network of interdomain contacts that links the DNA damage interface to the catalytic domain (CAT). The DNA damage-induced conformation of PARP-1 results in structural distortions that destabilize the CAT. Our results suggest that an increase in CAT protein dynamics underlies the DNA-dependent activation mechanism of PARP-1.