Telomeres are nucleoprotein complexes that play essential roles in protecting chromosome ends. Mammalian telomeres consist of repetitive DNA sequences bound by the shelterin complex. In this complex, the POT1-TPP1 heterodimer binds to single-stranded telomeric DNAs, while TRF1 and TRF2-RAP1 interact with double-stranded telomeric DNAs. TIN2, the linchpin of this complex, simultaneously interacts with TRF1, TRF2, and TPP1 to mediate the stable assembly of the shelterin complex. However, the molecular mechanism by which TIN2 interacts with these proteins to orchestrate telomere protection remains poorly understood. Here, we report the crystal structure of the N-terminal domain of TIN2 in complex with TIN2-binding motifs from TPP1 and TRF2, revealing how TIN2 interacts cooperatively with TPP1 and TRF2. Unexpectedly, TIN2 contains a telomeric repeat factor homology (TRFH)-like domain that functions as a protein-protein interaction platform. Structure-based mutagenesis analyses suggest that TIN2 plays an important role in maintaining the stable shelterin complex required for proper telomere end protection.

中文翻译：

---

哺乳动物 TIN2-TPP1-TRF2 端粒复合物的结构和功能分析。

端粒是核蛋白复合物，在保护染色体末端方面发挥重要作用。哺乳动物端粒由 shelterin 复合物结合的重复 DNA 序列组成。在这个复合物中，POT1-TPP1 异二聚体与单链端粒 DNA 结合，而 TRF1 和 TRF2-RAP1 与双链端粒 DNA 相互作用。TIN2 是该复合体的关键，同时与 TRF1、TRF2 和 TPP1 相互作用，以介导 shelterin 复合体的稳定组装。然而，TIN2 与这些蛋白质相互作用以协调端粒保护的分子机制仍然知之甚少。在这里，我们报告了 TIN2 N 末端结构域与来自 TPP1 和 TRF2 的 TIN2 结合基序复合物的晶体结构，揭示了 TIN2 如何与 TPP1 和 TRF2 协同相互作用。不料，TIN2 包含一个类似端粒重复因子同源性 (TRFH) 的结构域，可作为蛋白质-蛋白质相互作用平台。基于结构的诱变分析表明，TIN2 在维持适当的端粒末端保护所需的稳定 shelterin 复合物方面起着重要作用。