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| Item Type: | Article |
|---|---|
| Title: | Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5' exonuclease-mediated nucleic acid degradation |
| Creators Name: | Roske, Y. and Cappel, C. and Cremer, N. and Hoffmann, P. and Koudelka, T. and Tholey, A. and Heinemann, U. and Daumke, O. and Damme, M. |
| Abstract: | The phospholipase D (PLD) family is comprised of enzymes bearing phospholipase activity towards lipids or endo- and exonuclease activity towards nucleic acids. PLD3 is synthesized as a type II transmembrane protein and proteolytically cleaved in lysosomes, yielding a soluble active form. The deficiency of PLD3 leads to the slowed degradation of nucleic acids in lysosomes and chronic activation of nucleic acid-specific intracellular toll-like receptors. While the mechanism of PLD phospholipase activity has been extensively characterized, not much is known about how PLDs bind and hydrolyze nucleic acids. Here, we determined the high-resolution crystal structure of the luminal N-glycosylated domain of human PLD3 in its apo- and single-stranded DNA-bound forms. PLD3 has a typical phospholipase fold and forms homodimers with two independent catalytic centers via a newly identified dimerization interface. The structure of PLD3 in complex with an ssDNA-derived thymidine product in the catalytic center provides insights into the substrate binding mode of nucleic acids in the PLD family. Our structural data suggest a mechanism for substrate binding and nuclease activity in the PLD family and provide the structural basis to design immunomodulatory drugs targeting PLD3. |
| Keywords: | PLD3, Structural Biology, Lysosome, Dna/Rna Degradation, Phospholipase D, 5' Exonuclease |
| Source: | Nucleic Acids Research |
| ISSN: | 0305-1048 |
| Publisher: | Oxford University Press |
| Volume: | 52 |
| Number: | 1 |
| Page Range: | 370-384 |
| Date: | 11 January 2024 |
| Official Publication: | https://doi.org/10.1093/nar/gkad1114 |
| PubMed: | View item in PubMed |
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