National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.
Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, China.
Cell Res. 2017 Dec;27(12):1503-1520. doi: 10.1038/cr.2017.145. Epub 2017 Nov 21.
Telomeric shelterin complex caps chromosome ends and plays a crucial role in telomere maintenance and protection. In the fission yeast Schizosaccharomyces pombe, shelterin is composed of telomeric single- and double-stranded DNA-binding protein subcomplexes Pot1-Tpz1 and Taz1-Rap1, which are bridged by their interacting protein Poz1. However, the structure of Poz1 and how Poz1 functions as an interaction hub in the shelterin complex remain unclear. Here we report the crystal structure of Poz1 in complex with Poz1-binding motifs of Tpz1 and Rap1. The crystal structure shows that Poz1 employs two different binding surfaces to interact with Tpz1 and Rap1. Unexpectedly, the structure also reveals that Poz1 adopts a dimeric conformation. Mutational analyses suggest that proper interactions between Tpz1, Poz1, and Rap1 in the shelterin core complex are required for telomere length homeostasis and heterochromatin structure maintenance at telomeres. Structural resemblance between Poz1 and the TRFH domains of other shelterin proteins in fission yeast and humans suggests a model for the evolution of shelterin proteins.
端粒庇护体复合物覆盖染色体末端，在端粒维持和保护中发挥关键作用。在裂殖酵母 Schizosaccharomyces pombe 中，庇护体由端粒单链和双链 DNA 结合蛋白亚基复合物 Pot1-Tpz1 和 Taz1-Rap1 组成，它们通过相互作用蛋白 Poz1 桥接。然而，Poz1 的结构以及 Poz1 如何作为庇护体复合物中的相互作用中心发挥作用尚不清楚。在这里，我们报告了 Poz1 与 Tpz1 和 Rap1 的 Poz1 结合基序复合物的晶体结构。晶体结构显示，Poz1 采用两种不同的结合表面与 Tpz1 和 Rap1 相互作用。出乎意料的是，该结构还揭示了 Poz1 采用二聚体构象。突变分析表明，庇护体核心复合物中 Tpz1、Poz1 和 Rap1 之间的适当相互作用对于端粒长度动态平衡和端粒处异染色质结构的维持是必需的。Poz1 与裂殖酵母和人类其他庇护体蛋白的 TRFH 结构域之间的结构相似性表明了庇护体蛋白进化的模型。
