Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA
Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA
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DOI：
10.1038/nature03927
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发表时间：
2005-09-15
期刊：
影响因子：
64.8
通讯作者：
Dekker, C
中科院分区：
文献类型：
--
作者：
Moreno-Herrero, F;de Jager, M;Dekker, C
人类Rad 50/Mre 11/Nbs 1复合物（hR/M/N）通过指导DNA末端的正确加工（包括DNA断裂），作为基因组完整性的重要监护人发挥作用（1）。这种生物学功能是由于它能够束缚断裂的DNA分子（2，3）。hR/M/N的动态分子结构由一个球状DNA结合结构域组成，从该结构域突出两个50 nm长的卷曲螺旋。盘绕的线圈是柔性的（4），并且它们的顶点可以自缔合（5）。盘绕线圈的柔性允许它们的顶点采用有利于相互作用的取向。然而，这也允许在同一复合物内的两个卷曲螺旋的尖端之间的相互作用，这与DNA拴系所需的复合物间相互作用竞争并使其受挫。在这里，我们表明，动态架构的hR/M/N显着影响DNA结合。通过hR/M/N球状结构域的DNA结合导致卷曲螺旋的平行取向;这防止了复合物内的相互作用，并有利于DNA束缚所需的复合物间的关联。因此，hR/M/N复合物是生物纳米机器的一个例子，其中与其配体（在这种情况下是DNA）的结合影响位于50 nm远的结构域的功能构象。
The human Rad50/Mre11/Nbs1 complex (hR/M/N) functions as an essential guardian of genome integrity by directing the proper processing of DNA ends, including DNA breaks(1). This biological function results from its ability to tether broken DNA molecules(2,3). hR/M/N's dynamic molecular architecture consists of a globular DNA-binding domain from which two 50-nm-long coiled coils protrude. The coiled coils are flexible(4) and their apices can self-associate(5). The flexibility of the coiled coils allows their apices to adopt an orientation favourable for interaction. However, this also allows interaction between the tips of two coiled coils within the same complex, which competes with and frustrates the intercomplex interaction required for DNA tethering. Here we show that the dynamic architecture of hR/M/N is markedly affected by DNA binding. DNAbinding by the hR/M/N globular domain leads to parallel orientation of the coiled coils; this prevents intracomplex interactions and favours intercomplex associations needed for DNA tethering. The hR/M/N complex thus is an example of a biological nanomachine in which binding to its ligand, in this case DNA, affects the functional conformation of a domain located 50 nm distant.