A structurally conserved human and Tetrahymena telomerase catalytic core

Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31078-31087. doi: 10.1073/pnas.2011684117. Epub 2020 Nov 23.

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.

Keywords: TERT; TPP1; electron microscopy; reverse transcriptase; telomere.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Catalytic Domain / genetics
  • Cryoelectron Microscopy
  • Humans
  • Protein Binding
  • Protein Conformation
  • Protein Domains / genetics
  • RNA / genetics
  • RNA / ultrastructure*
  • Sequence Alignment
  • Structural Homology, Protein
  • Telomerase / genetics
  • Telomerase / ultrastructure*
  • Tetrahymena thermophila / enzymology
  • Tetrahymena thermophila / ultrastructure*
  • Tribolium / enzymology

Substances

  • telomerase RNA
  • RNA
  • TERT protein, human
  • Telomerase