Telomere elongation through telomerase enables chromosome survival during cellular proliferation. The conserved multifunctional shelterin complex associates with telomeres to coordinate multiple telomere activities, including telomere elongation by telomerase. Similar to the human shelterin, fission yeast shelterin is composed of telomeric sequence-specific double- and single-stranded DNA-binding proteins, Taz1 and Pot1, respectively, bridged by Rap1, Poz1, and Tpz1. Here, we report the crystal structure of the fission yeast Tpz1^475-508-Poz1-Rap1^467-496 complex that provides the structural basis for shelterin bridge assembly. Biochemical analyses reveal that shelterin bridge assembly is a hierarchical process in which Tpz1 binding to Poz1 elicits structural changes in Poz1, allosterically promoting Rap1 binding to Poz1. Perturbation of the cooperative Tpz1-Poz1-Rap1 assembly through mutation of the “conformational trigger” in Poz1 leads to unregulated telomere lengthening. Furthermore, we find that the human shelterin counterparts TPP1-TIN2-TRF2 also assemble hierarchically, indicating cooperativity as a conserved driving force for shelterin assembly.

通过端粒酶延长端粒使染色体在细胞增殖过程中存活。保守的多功能庇护素复合物与端粒结合以协调多种端粒活动，包括端粒酶对端粒的延长。与人类shelterin 类似，裂变酵母shelterin 由端粒序列特异性双链和单链DNA 结合蛋白Taz1 和Pot1 组成，分别由Rap1、Poz1 和Tpz1 桥接。在这里，我们报告了裂变酵母 Tpz1 ^475-508 -Poz1-Rap1 ^{467-496的晶体结构}为遮蔽桥组装提供结构基础的综合体。生化分析表明，shelterin 桥组装是一个分层过程，其中 Tpz1 与 Poz1 的结合引发 Poz1 的结构变化，变构促进 Rap1 与 Poz1 的结合。通过 Poz1 中“构象触发器”的突变对协同 Tpz1-Poz1-Rap1 组装的扰动导致不受调节的端粒延长。此外，我们发现人类庇护所对应物 TPP1-TIN2-TRF2 也分层组装，表明协同性是庇护所组装的保守驱动力。