State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Howard Hughes Medical Institute, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
Cell Rep. 2013 Sep 12;4(5):861-9. doi: 10.1016/j.celrep.2013.08.017. Epub 2013 Sep 5.
SLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure of the TRF2-binding motif of SLX4 (SLX4TBM) in complex with the TRFH domain of TRF2 (TRF2TRFH) and map the interactions of SLX4 with endonucleases SLX1, XPF, and MUS81. TRF2 recognizes a unique HxLxP motif on SLX4 via the peptide-binding site in its TRFH domain. Telomeric localization of SLX4 and associated nucleases depend on the SLX4-endonuclease and SLX4-TRF2 interactions and the protein levels of SLX4 and TRF2. SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. We propose that the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance.
SLX4 与几种内切酶相互作用，以解决 DNA 代谢中的结构障碍。SLX4 还在人类细胞中与端粒蛋白 TRF2 相互作用。这些在端粒上的相互作用的分子机制尚不清楚。在这里，我们报告了 SLX4 的 TRF2 结合基序（SLX4TBM）与 TRF2 的 TRFH 结构域（TRF2TRFH）复合物的晶体结构，并绘制了 SLX4 与内切酶 SLX1、XPF 和 MUS81 的相互作用图。TRF2 通过其 TRFH 结构域中的肽结合位点识别 SLX4 上独特的 HxLxP 基序。SLX4 和相关核酸酶的端粒定位依赖于 SLX4-内切酶和 SLX4-TRF2 相互作用以及 SLX4 和 TRF2 的蛋白水平。SLX4 组装了一个内切酶工具包，通过 SLX1 催化的核切割来负调控端粒 DNA 结构，从而调节端粒长度。我们提出，SLX4-TRF2 复合物作为一个双层支架，将多个内切酶与端粒桥接起来，用于基于重组的端粒维持。
