A structurally conserved human and Tetrahymena telomerase catalytic core
- 23 November 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (49), 31078-31087
- https://doi.org/10.1073/pnas.2011684117
Abstract
Telomerase is a ribonucleoprotein complex that counteracts the shortening of chromosome ends due to incomplete replication. Telomerase contains a catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER). However, what defines TERT and separates it from other reverse transcriptases remains a subject of debate. A recent cryoelectron microscopy map of Tetrahymena telomerase revealed the structure of a previously uncharacterized TERT domain (TRAP) with unanticipated interactions with the telomerase essential N-terminal (TEN) domain and roles in telomerase activity. Both TEN and TRAP are absent in the putative Tribolium TERT that has been used as a model for telomerase for over a decade. To investigate the conservation of TRAP and TEN across species, we performed multiple sequence alignments and statistical coupling analysis on all identified TERTs and find that TEN and TRAP have coevolved as telomerase-specific domains. Integrating the data from bioinformatic analysis and the structure of Tetrahymena telomerase, we built a pseudoatomic model of human telomerase catalytic core that accounts for almost all of the cryoelectron microscopy density in a published map, including TRAP in previously unassigned density as well as telomerase RNA domains essential for activity. This more complete model of the human telomerase catalytic core illustrates how domains of TER and TERT, including the TEN–TRAP complex, can interact in a conserved manner to regulate telomere synthesis.Funding Information
- HHS | National Institutes of Health (GM048123)
- HHS | National Institutes of Health (GM131901)
This publication has 101 references indexed in Scilit:
- The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivityNature, 2012
- The telomere syndromesNature Reviews Genetics, 2012
- The RNA accordion model for template positioning by telomerase RNA during telomeric DNA synthesisNature Structural & Molecular Biology, 2011
- Human Telomerase Domain Interactions Capture DNA for TEN Domain-Dependent Processive ElongationMolecular Cell, 2011
- Structurally conserved five nucleotide bulge determines the overall topology of the core domain of human telomerase RNAProceedings of the National Academy of Sciences of the United States of America, 2010
- Protein Sectors: Evolutionary Units of Three-Dimensional StructureCell, 2009
- Telomere-associated endonuclease-deficient Penelope -like retroelements in diverse eukaryotesProceedings of the National Academy of Sciences of the United States of America, 2007
- Adult-onset pulmonary fibrosis caused by mutations in telomeraseProceedings of the National Academy of Sciences of the United States of America, 2007
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- T-coffee: a novel method for fast and accurate multiple sequence alignmentJournal of Molecular Biology, 2000