2025-12-19 東京大学
PLD3 による一本鎖 DNA の認識
<関連情報>
- https://www.u-tokyo.ac.jp/focus/ja/press/z0111_00093.html
- https://www.u-tokyo.ac.jp/content/400276787.pdf
- https://www.nature.com/articles/s41467-025-66261-2
構造スナップショットからリソソームエキソヌクレアーゼPLD3とPLD4による一本鎖DNA分解のメカニズムの洞察 Mechanistic insights into single-stranded DNA degradation by lysosomal exonucleases PLD3 and PLD4 from structural snapshots
Yoshinori Hirano,Wakiko Ezaki,Ryota Sato,Umeharu Ohto,Kensuke Miyake & Toshiyuki Shimizu
Nature Communications Published:11 December 2025
DOI:https://doi.org/10.1038/s41467-025-66261-2
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
Abstract
Lysosomal exonuclease phospholipase D (PLD) family PLD3 and PLD4 degrade single-stranded RNA or DNA and regulate TLR7 or TLR9 responses. Polymorphisms of these enzymes are associated with human diseases: PLD4 is associated with inflammatory diseases, and PLD3 is associated with neurodegenerative diseases. Here, we determine the structures of substrate-bound PLD3 and PLD4 by cryo-electron microscopy. Our structures reveal that PLD3 rebuilds a substrate-binding pocket, depending on the substrate, mainly via motion of the Phe335-containing loop. Furthermore, we captured the structure in a metastable state that appears during substrate rearrangement following product release. Together, our findings identify the residues that underlie the distinct activities of PLD3 and PLD4. This study provides a mechanistic basis for the exonuclease activity of PLD3 and PLD4 in single-stranded DNA degradation.
