7V9A

biogenesis module of human telomerase holoenzyme

7V9A の概要

• エントリーDOI: 10.2210/pdb7v9a/pdb
• EMDBエントリー: 31811 31813
• 分子名称: Telomerase Cajal body protein 1, H/ACA ribonucleoprotein complex subunit DKC1, H/ACA ribonucleoprotein complex subunit 1, ... (6 entities in total)
• 機能のキーワード: telomerase, replication
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 415061.33

構造登録者

Wan, F.,Ding, Y.,Yang, L.,Wu, Z.,Wu, J.,Lei, M. (登録日: 2021-08-24, 公開日: 2022-03-30, 最終更新日: 2024-06-12)

主引用文献

Wan, F.,Ding, Y.,Zhang, Y.,Wu, Z.,Li, S.,Yang, L.,Yan, X.,Lan, P.,Li, G.,Wu, J.,Lei, M.
Zipper head mechanism of telomere synthesis by human telomerase.
Cell Res., 31:1275-1290, 2021

PubMed Abstract: Telomerase, a multi-subunit ribonucleoprotein complex, is a unique reverse transcriptase that catalyzes the processive addition of a repeat sequence to extend the telomere end using a short fragment of its own RNA component as the template. Despite recent structural characterizations of human and Tetrahymena telomerase, it is still a mystery how telomerase repeatedly uses its RNA template to synthesize telomeric DNA. Here, we report the cryo-EM structure of human telomerase holoenzyme bound with telomeric DNA at resolutions of 3.5 Å and 3.9 Å for the catalytic core and biogenesis module, respectively. The structure reveals that a leucine residue Leu980 in telomerase reverse transcriptase (TERT) catalytic subunit functions as a zipper head to limit the length of the short primer-template duplex in the active center. Moreover, our structural and computational analyses suggest that TERT and telomerase RNA (hTR) are organized to harbor a preformed active site that can accommodate short primer-template duplex substrates for catalysis. Furthermore, our findings unveil a double-fingers architecture in TERT that ensures nucleotide addition processivity of human telomerase. We propose that the zipper head Leu980 is a structural determinant for the sequence-based pausing signal of DNA synthesis that coincides with the RNA element-based physical template boundary. Functional analyses unveil that the non-glycine zipper head plays an essential role in both telomerase repeat addition processivity and telomere length homeostasis. In addition, we also demonstrate that this zipper head mechanism is conserved in all eukaryotic telomerases. Together, our study provides an integrated model for telomerase-mediated telomere synthesis.

PubMed: 34782750
DOI: 10.1038/s41422-021-00586-7

実験手法

ELECTRON MICROSCOPY (3.94 Å)