Structural Biology

The Schlafen (SLFN) family, part of the interferon-stimulated genes, plays roles in cell cycle regulation, T cell quiescence, viral replication inhibition, DNA repair, and tRNA processing. Human SLFN11 sensitizes cells to DNA-damaging agents by irreversibly blocking stalled replication forks, making it a potential chemotherapy biomarker. It also acts as a pattern recognition receptor for single-stranded DNA (ssDNA) and restricts viruses by targeting translation via codon-usage-dependent endoribonuclease activity.

Katja Lammens, Michael Kugler, and Felix Metzner present cryo-EM structures of SLFN11 bound to tRNA-Leu and tRNA-Met, revealing insights into tRNA binding, cleavage, and phosphorylation-based regulation. Phosphomimetic mutant S753D adopts a monomeric conformation, binds ATP, but loses ssDNA binding and ribonuclease activity, highlighting S753 as a conformational switch regulating dimerization, ATP/ssDNA binding, while S219 and T230 control tRNA recognition and nuclease activity.

Original publication:

Phosphorylation-mediated conformational change regulates human SLFN11
Kugler M, Metzner FJ, Witte G, Hopfner KP, Lammens K
Nature Communications 15, 10500 Dec 03, 2024, https://doi.org/10.1038/s41467-024-54833-7