Seminar

Molecular basis of tRNA recognition by the Elongator complex

María Ibarra Daudén, PhD

The highly conserved Elongator complex modifies transfer RNAs (tRNAs) in their wobble base position, thereby regulating protein synthesis and ensuring proteome stability. Genetic depletion or specific mutations affecting the integrity and activity of the Elongator complex are associated with the onset of severe neurodegenerative diseases, intellectual disabilities, and cancer. However, the precise mechanisms of tRNA recognition and its modification reaction remain elusive. Here we show cryo–electron microscopy structures of the catalytic subcomplex of Elongator and its tRNA-bound state at 3.3 and 4.4 Å resolution respectively. The structures resolve details of the catalytic site, including the substrate tRNA, the iron-sulfur cluster and a SAM molecule, which are all validated by mutational analyses in vitro and in vivo. tRNA binding induces conformational rearrangements, which precisely position the targeted anticodon base in the active site. Our results provide the molecular basis for substrate recognition of Elongator, essential to understand its cellular function and role in neurodegenerative diseases and cancer.