PLD3 8V05: BI3323-Aug2025

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== Summary ==
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== Introduction ==
Phospholipase D3 (PLD3) is an enzyme found inside endolysosomes, where it helps clear out stray single-stranded DNA and RNA before they can trigger immune alarms. The structure shown here (PDB 8V05) represents the soluble luminal portion of mouse PLD3, which closely reflects the behaviour of human PLD4.
Phospholipase D3 (PLD3) is an enzyme found inside endolysosomes, where it helps clear out stray single-stranded DNA and RNA before they can trigger immune alarms. The structure shown here (PDB 8V05) represents the soluble luminal portion of mouse PLD3, which closely reflects the behaviour of human PLD4.
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The crystal structure of mouse PLD3 (PDB ID: 8V05) reveals a pseudo-dimeric architecture consisting of two structurally similar domains, Domain A (residues 69–254) and Domain B (residues 277–488), connected by a flexible linker (residues 255–276). Both domains contain β-sheets. In the first image (Overall Structure), domain A is marked with green and domain B with orange, with a pink linker bridging them. Their interface is involved in catalysis.
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The crystal structure of mouse PLD3 (PDB ID: 8V05) reveals a pseudo-dimeric architecture consisting of two structurally similar domains, Domain A (residues 69–254) and Domain B (residues 277–488), connected by a flexible linker (residues 255–276). Both domains contain β-sheets. In the first image (Overall structure of PLD3 (PDB 8V05)), domain A is marked with green and domain B with orange, with a pink linker bridging them. Their interface is involved in catalysis.
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PLD3 uses two conserved HKD motifs to break down genetic material. The first motif (H199, K201, D206) lies in Domain A, and the second (H414, K416, E421) sits in Domain B. Together, they build a positively charged pocket that draws in the negatively charged phosphates of DNA/RNA. Evidence from structural studies suggests that H414 performs the key attack on the phosphodiester bond, briefly forming a phosphohistidine intermediate. H199 from Domain A serves as a proton shuttle, facilitates hydrolysis of this intermediate by activating a water molecule, releasing a single 3′-phosphate nucleotide and regenerating the enzyme. PLD3 also exhibits weak phosphatase activity toward 5′-phosphorylated nucleic acids, whereby H414 captures the 5′ phosphate to form the phosphohistidine intermediate, which is subsequently hydrolyzed to release inorganic phosphate. This phosphatase activity inhibits exonuclease function by trapping the enzyme in the covalent intermediate state. The second image (Active Site) highlights the HKD1 in blue and HKD2 in red.
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Mutations that weaken PLD3’s structure or activity are linked to inflammatory and neurodegenerative disorders.
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'''BI3323-Aug2025'''
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== Structural highlights ==
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PLD3 uses two conserved HKD motifs to break down genetic material. The first motif (H199, K201, D206) lies in Domain A, and the second (H414, K416, E421) sits in Domain B. Together, they build a positively charged pocket that draws in the negatively charged phosphates of DNA/RNA. Evidence from structural studies suggests that H414 performs the key attack on the phosphodiester bond, briefly forming a phosphohistidine intermediate. H199 from Domain A serves as a proton shuttle, facilitates hydrolysis of this intermediate by activating a water molecule, releasing a single 3′-phosphate nucleotide and regenerating the enzyme. PLD3 also exhibits weak phosphatase activity toward 5′-phosphorylated nucleic acids, whereby H414 captures the 5′ phosphate to form the phosphohistidine intermediate, which is subsequently hydrolyzed to release inorganic phosphate. This phosphatase activity inhibits exonuclease function by trapping the enzyme in the covalent intermediate state. The second image (HKD catalytic center of PLD3) highlights the catalytic histidines of HKD1 in blue and HKD2 in red.
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== 3D Scenes ==
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== Significance ==
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{{Mrignaki_PLD3_8V05:Overall_Structure}}
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PLD3 is an endolysosomal nuclease linked to neuronal health and late-onset Alzheimer’s disease. Its dysfunction leads to impaired nucleic-acid clearance and lysosomal stress.
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{{Mrignaki_PLD3_8V05:Active_Site}}
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== References ==
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Meng Yuan, Linghang Peng, Deli Huang, Amanda Gavin, Fangkun Luan, Jenny Tran, Ziqi Feng, Xueyong Zhu, Jeanne Matteson, Ian A. Wilson, and David Nemazee, Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4
== 3D Images ==
== 3D Images ==
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[[Image:PLD3_active.png|thumb|400px|HKD catalytic center of PLD3.]]
[[Image:PLD3_active.png|thumb|400px|HKD catalytic center of PLD3.]]
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== Scripts ==
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<Structure load='8V05' size='350' frame='true' align='right' caption='PDL3 (PDB ID: 8V05)' scene='Insert optional scene name here' />
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<pre>
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For the overall structure:
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load https://files.rcsb.org/download/8V05.pdb
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# Display the entire protein as ribbon structure
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select protein
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cartoon on
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# Explicitly hide sticks for all protein residues to ensure no sticks appear in domain regions
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select protein
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hide sticks
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# Color the domains
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select 69-254
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color green
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select 277-488
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color orange
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select 255-276
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color pink
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# Show ball-and-stick representation ONLY for the active site residues
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select 199,201,206,414,416,421
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show sticks
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spacefill 100%
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# Color the active site residues to distinguish which domain they belong to
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select 199,201,206
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color blue
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select 414,416,421
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color red
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# Add labels to the most important catalytic histidines
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select 199
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label "H199"
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# Set all labels to white for better visibility
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color labels white
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select 414
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label "H414"
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# Set all labels to white for better visibility
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color labels white
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# Center the view on the active site
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center 199,414
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zoom 120
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For the active sites only:
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load https://files.rcsb.org/download/8V05.pdb
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# Explicitly show the protein first, then selectively hide other regions
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show protein
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# Hide everything except the regions containing the catalytic sites
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hide not (190-220 or 405-435)
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# Show the selected regions as sticks
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select 190-220 or 405-435
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show sticks
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# Make the key catalytic residues more prominent with larger spheres
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select 199, 201, 206, 414, 416, 421
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spacefill 150%
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# Color the catalytic residues from the two HKD motifs differently
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select 199, 201, 206
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color blue
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select 414, 416, 421
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color red
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# Add labels to the key catalytic histidines
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select 199
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label "H199"
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# Set all labels to white for better visibility
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color labels white
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select 414
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label "H414"
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# Set all labels to white for better visibility
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color labels white
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# Center the view on the active site
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center 199, 414
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zoom 120
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</pre>
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Current revision

Contents

Introduction

Phospholipase D3 (PLD3) is an enzyme found inside endolysosomes, where it helps clear out stray single-stranded DNA and RNA before they can trigger immune alarms. The structure shown here (PDB 8V05) represents the soluble luminal portion of mouse PLD3, which closely reflects the behaviour of human PLD4. The crystal structure of mouse PLD3 (PDB ID: 8V05) reveals a pseudo-dimeric architecture consisting of two structurally similar domains, Domain A (residues 69–254) and Domain B (residues 277–488), connected by a flexible linker (residues 255–276). Both domains contain β-sheets. In the first image (Overall structure of PLD3 (PDB 8V05)), domain A is marked with green and domain B with orange, with a pink linker bridging them. Their interface is involved in catalysis.

Structural highlights

PLD3 uses two conserved HKD motifs to break down genetic material. The first motif (H199, K201, D206) lies in Domain A, and the second (H414, K416, E421) sits in Domain B. Together, they build a positively charged pocket that draws in the negatively charged phosphates of DNA/RNA. Evidence from structural studies suggests that H414 performs the key attack on the phosphodiester bond, briefly forming a phosphohistidine intermediate. H199 from Domain A serves as a proton shuttle, facilitates hydrolysis of this intermediate by activating a water molecule, releasing a single 3′-phosphate nucleotide and regenerating the enzyme. PLD3 also exhibits weak phosphatase activity toward 5′-phosphorylated nucleic acids, whereby H414 captures the 5′ phosphate to form the phosphohistidine intermediate, which is subsequently hydrolyzed to release inorganic phosphate. This phosphatase activity inhibits exonuclease function by trapping the enzyme in the covalent intermediate state. The second image (HKD catalytic center of PLD3) highlights the catalytic histidines of HKD1 in blue and HKD2 in red.

Significance

PLD3 is an endolysosomal nuclease linked to neuronal health and late-onset Alzheimer’s disease. Its dysfunction leads to impaired nucleic-acid clearance and lysosomal stress.

References

Meng Yuan, Linghang Peng, Deli Huang, Amanda Gavin, Fangkun Luan, Jenny Tran, Ziqi Feng, Xueyong Zhu, Jeanne Matteson, Ian A. Wilson, and David Nemazee, Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4

3D Images

Overall structure of PLD3 (PDB 8V05).
Overall structure of PLD3 (PDB 8V05).
HKD catalytic center of PLD3.
HKD catalytic center of PLD3.

PDL3 (PDB ID: 8V05)

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

Mriganki Sarma

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