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Nature. 2018 May;557(7704):190-195. doi: 10.1038/s41586-018-0062-x. Epub 2018 Apr 25.

Cryo-EM structure of substrate-bound human telomerase holoenzyme.

Nguyen THD1,2,3,4, Tam J1, Wu RA1,5, Greber BJ2,3, Toso D2, Nogales E6,7,8,9, Collins K10,11.

Author information

1
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
2
California Institute for Quantitative Biology, University of California, Berkeley, CA, USA.
3
Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
4
Miller Institute for Basic Research in Science, University of California, Berkeley, CA, USA.
5
Harvard Medical School, Boston, MA, USA.
6
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA. enogales@lbl.gov.
7
California Institute for Quantitative Biology, University of California, Berkeley, CA, USA. enogales@lbl.gov.
8
Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. enogales@lbl.gov.
9
Howard Hughes Medical Institute, University of California, Berkeley, CA, USA. enogales@lbl.gov.
10
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA. kcollins@berkeley.edu.
11
California Institute for Quantitative Biology, University of California, Berkeley, CA, USA. kcollins@berkeley.edu.

Abstract

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.

PMID:
29695869
PMCID:
PMC6223129
DOI:
10.1038/s41586-018-0062-x
[Indexed for MEDLINE]
Free PMC Article

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