小柯机器人

美国加州大学洛杉矶分校Juli Feigon团队解析出活性的人类端粒酶与端粒保护蛋白TPP1的结构。相关论文于2022年4月13日在线发表于国际学术期刊《自然》。

研究人员报告了端粒酶逆转录酶（TERT）和端粒酶RNA（TER ，也称为hTR）的人类端粒酶催化核心冷冻电镜结构，以及带有外壳蛋白TPP1的端粒酶冷冻电镜结构。TPP1与TERT特有的端粒酶必需N端结构域（TEN）和TERT特有的端粒酶RAP基序（TRAP）形成结构化界面，并且TEN-TRAP的构象动力学在TPP1结合时受到抑制，这定义了对招募和激活的需求。这些结构进一步揭示了参与模板和端粒DNA处理的TERT和TER元件——包括TEN结构域和TRAP-拇指螺旋通道——在结构上与四膜虫端粒酶中的元件在很大程度上同源，并提供了对该机制的独特见解端粒酶活性。端粒酶抑制剂 BIBR1532的结合位点与TER假结和TERT拇指结构域之间的关键相互作用重叠。许多导致端粒病的突变位于TERT-TER和TEN-TRAP-TPP1界面，从而突出了TER-TERT和TPP1相互作用对端粒酶活性、招募和作为药物靶点的重要性。

据悉，人类端粒酶是一种RNA-蛋白质复合物，通过合成端粒重复TTAGGG1的多个拷贝来延伸线性染色体的3'端。它的活性是癌症进展、干细胞更新和细胞衰老的决定因素。端粒酶被招募到端粒并被端粒保护蛋白TPP1激活以进行端粒重复合成。人类端粒酶具有双叶结构，具有一个催化核心核糖核蛋白和一个H and ACA box核糖核蛋白。

附：英文原文

Title: Structure of active human telomerase with telomere shelterin protein TPP1

Author: Liu, Baocheng, He, Yao, Wang, Yaqiang, Song, He, Zhou, Z. Hong, Feigon, Juli

Issue&Volume: 2022-04-13

Abstract: Human telomerase is a RNA–protein complex that extends the 3′ end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG1. Its activity is a determinant of cancer progression, stem cell renewal and cellular aging2,3,4,5. Telomerase is recruited to telomeres and activated for telomere repeat synthesis by the telomere shelterin protein TPP16,7. Human telomerase has a bilobal structure with a catalytic core ribonuclear protein and a H and ACA box ribonuclear protein8,9. Here we report cryo-electron microscopy structures of human telomerase catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER (also known as hTR)), and of telomerase with the shelterin protein TPP1. TPP1 forms a structured interface with the TERT-unique telomerase essential N-terminal domain (TEN) and the telomerase RAP motif (TRAP) that are unique to TERT, and conformational dynamics of TEN–TRAP are damped upon TPP1 binding, defining the requirements for recruitment and activation. The structures further reveal that the elements of TERT and TER that are involved in template and telomeric DNA handling—including the TEN domain and the TRAP–thumb helix channel—are largely structurally homologous to those in Tetrahymena telomerase10, and provide unique insights into the mechanism of telomerase activity. The binding site of the telomerase inhibitor BIBR153211,12 overlaps a critical interaction between the TER pseudoknot and the TERT thumb domain. Numerous mutations leading to telomeropathies13,14 are located at the TERT–TER and TEN–TRAP–TPP1 interfaces, highlighting the importance of TER–TERT and TPP1 interactions for telomerase activity, recruitment and as drug targets.

DOI: 10.1038/s41586-022-04582-8

Source: https://www.nature.com/articles/s41586-022-04582-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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