Center for Integrated Protein Science Munich, Ludwig-Maximilians-University Munich, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
Cell. 2011 Apr 1;145(1):54-66. doi: 10.1016/j.cell.2011.02.038.
The MR (Mre11 nuclease and Rad50 ABC ATPase) complex is an evolutionarily conserved sensor for DNA double-strand breaks, highly genotoxic lesions linked to cancer development. MR can recognize and process DNA ends even if they are blocked and misfolded. To reveal its mechanism, we determined the crystal structure of the catalytic head of Thermotoga maritima MR and analyzed ATP-dependent conformational changes. MR adopts an open form with a central Mre11 nuclease dimer and two peripheral Rad50 molecules, a form suited for sensing obstructed breaks. The Mre11 C-terminal helix-loop-helix domain binds Rad50 and attaches flexibly to the nuclease domain, enabling large conformational changes. ATP binding to the two Rad50 subunits induces a rotation of the Mre11 helix-loop-helix and Rad50 coiled-coil domains, creating a clamp conformation with increased DNA-binding activity. The results suggest that MR is an ATP-controlled transient molecular clamp at DNA double-strand breaks.
MR（Mre11 核酸酶和 Rad50 ABC ATP 酶）复合物是一种进化上保守的 DNA 双链断裂传感器，与癌症发展密切相关的高度遗传毒性损伤。MR 即使在 DNA 末端被阻断和错误折叠的情况下，也能识别和处理 DNA 末端。为了揭示其机制，我们确定了耐热海洋栖热菌 MR 的催化头部的晶体结构，并分析了 ATP 依赖性构象变化。MR 采用一种开放形式，具有中央 Mre11 核酸酶二聚体和两个外周 Rad50 分子，这种形式适合感应受阻的断裂。Mre11 C 端螺旋-环-螺旋结构域与 Rad50 结合，并灵活地附着在核酸酶结构域上，使大的构象变化成为可能。ATP 结合到两个 Rad50 亚基上，诱导 Mre11 螺旋-环-螺旋和 Rad50 卷曲螺旋结构域的旋转，形成具有增加的 DNA 结合活性的夹合构象。结果表明，MR 是 DNA 双链断裂处的一种 ATP 控制的瞬时分子夹。
