replication fork arrest / negative regulation of G1/S transition of mitotic cell cycle / negative regulation of DNA replication / site of DNA damage / immune system process / helicase activity / endonuclease activity / defense response to virus / 加水分解酵素; エステル加水分解酵素 / tRNA binding ...replication fork arrest / negative regulation of G1/S transition of mitotic cell cycle / negative regulation of DNA replication / site of DNA damage / immune system process / helicase activity / endonuclease activity / defense response to virus / 加水分解酵素; エステル加水分解酵素 / tRNA binding / chromatin remodeling / DNA damage response / ATP hydrolysis activity / DNA binding / nucleoplasm / ATP binding / nucleus / cytosol 類似検索 - 分子機能
ジャーナル: Nat Commun / 年: 2024 タイトル: Phosphorylation-mediated conformational change regulates human SLFN11. 著者: Michael Kugler / Felix J Metzner / Gregor Witte / Karl-Peter Hopfner / Katja Lammens / 要旨: 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, ...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.