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Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5' exonuclease-mediated nucleic acid degradation

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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., Cappel, C., Cremer, N., Hoffmann, P., Koudelka, T., Tholey, A., Heinemann, U., 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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