9GMW

SLFN11 WT dimer bound to tRNA-Leu-TAA (pre-cleavage state)

Summary for 9GMW

• Entry DOI: 10.2210/pdb9gmw/pdb
• Related: 9ERD 9ERE 9ERF
• EMDB information: 51456
• Descriptor: Schlafen family member 11, RNA (86-MER), ZINC ION, ... (5 entities in total)
• Functional Keywords: trna, endoribonuclease activity, dimeric, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 240509.14

Authors

Kugler, M.,Metzner, F.J.,Lammens, K. (deposition date: 2024-08-29, release date: 2024-12-11, Last modification date: 2024-12-18)

Primary citation

Kugler, M.,Metzner, F.J.,Witte, G.,Hopfner, K.P.,Lammens, K.
Phosphorylation-mediated conformational change regulates human SLFN11.
Nat Commun, 15:10500-10500, 2024

PubMed Abstract: Human Schlafen 11 (SLFN11) is sensitizing cells to DNA damaging agents by irreversibly blocking stalled replication forks, making it a potential predictive biomarker in chemotherapy. Furthermore, SLFN11 acts as a pattern recognition receptor for single-stranded DNA (ssDNA) and functions as an antiviral restriction factor, targeting translation in a codon-usage-dependent manner through its endoribonuclease activity. However, the regulation of the various SLFN11 functions and enzymatic activities remains enigmatic. Here, we present cryo-electron microscopy (cryo-EM) structures of SLFN11 bound to tRNA-Leu and tRNA-Met that give insights into tRNA binding and cleavage, as well as its regulation by phosphorylation at S219 and T230. SLFN11 phosphomimetic mutant S753D adopts a monomeric conformation, shows ATP binding, but loses its ability to bind ssDNA and shows reduced ribonuclease activity. Thus, the phosphorylation site S753 serves as a conformational switch, regulating SLFN11 dimerization, as well as ATP and ssDNA binding, while S219 and T230 regulate tRNA recognition and nuclease activity.

PubMed: 39627193
DOI: 10.1038/s41467-024-54833-7

Experimental method

ELECTRON MICROSCOPY (3 Å)