Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
California Institute for Quantitative Biology, University of California, Berkeley, CA, USA.
Nature. 2018 May;557(7704):190-195. doi: 10.1038/s41586-018-0062-x. Epub 2018 Apr 25.
The enzyme telomerase adds telomeric repeats to chromosome ends to balance the loss of telomeres during genome replication. Telomerase regulation has been implicated in cancer, other human diseases, and ageing, but progress towards clinical manipulation of telomerase has been hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of the substrate-bound human telomerase holoenzyme at subnanometre resolution, showing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP). In the catalytic core, RNA encircles TERT, adopting a well-ordered tertiary structure with surprisingly limited protein-RNA interactions. The H/ACA RNP lobe comprises two sets of heterotetrameric H/ACA proteins and one Cajal body protein, TCAB1, representing a pioneering structure of a large eukaryotic family of ribosome and spliceosome biogenesis factors. Our findings provide a structural framework for understanding human telomerase disease mutations and represent an important step towards telomerase-related clinical therapeutics.
端粒酶将端粒重复序列添加到染色体末端，以平衡基因组复制过程中端粒的丢失。端粒酶的调节与癌症、其他人类疾病和衰老有关，但由于缺乏结构数据，端粒酶的临床操作进展一直受到阻碍。在这里，我们以亚纳米分辨率呈现了结合底物的人端粒酶全酶的冷冻电子显微镜结构，显示了两个灵活的 RNA 连接的叶状结构：具有端粒酶逆转录酶（TERT）和端粒酶 RNA（hTR）保守基序的催化核心，以及一个 H/ACA 核糖核蛋白（RNP）。在催化核心中，RNA 环绕 TERT，形成一个有序的三级结构，与 RNA 结合的蛋白之间的相互作用非常有限。H/ACA RNP 叶状结构由两组异四聚体的 H/ACA 蛋白和一个 Cajal 体蛋白 TCAB1 组成，代表了核糖体和剪接体生物发生因子这一大型真核家族的开创性结构。我们的研究结果为理解人类端粒酶疾病突变提供了结构框架，并代表了朝着与端粒酶相关的临床治疗迈进的重要一步。
