8Q1X

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

Summary for 8Q1X

• Entry DOI: 10.2210/pdb8q1x/pdb
• Descriptor: 5'-3' exonuclease PLD3, alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: pld3, structural biology, lysosome, dna/rna degradation, phospholipase d, 5' exonuclease, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 102486.68

Authors

Roske, Y.,Daumke, O.,Damme, M. (deposition date: 2023-08-01, release date: 2023-12-06, Last modification date: 2024-01-24)

Primary citation

Roske, Y.,Cappel, C.,Cremer, N.,Hoffmann, P.,Koudelka, T.,Tholey, A.,Heinemann, U.,Daumke, O.,Damme, M.
Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5' exonuclease-mediated nucleic acid degradation.
Nucleic Acids Res., 52:370-384, 2024

PubMed 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.

PubMed: 37994783
DOI: 10.1093/nar/gkad1114

Experimental method

X-RAY DIFFRACTION (1.85 Å)