Phospholipase D family member 5 (PLD5) is a poorly characterized member of the PLD superfamily. Despite containing the characteristic PLD phosphodiesterase domains with HKD motifs, PLD5 is considered catalytically inactive as a phospholipase because it lacks conserved active site residues required for phospholipid hydrolysis. UniProt explicitly names this protein "Inactive phospholipase D5". The protein is a type II single-pass transmembrane protein (~536 amino acids, ~61 kDa) that lacks the PX and PH domains found in classical PLD1/PLD2. Expression is enriched in brain and choroid plexus. Subcellular localization studies suggest mitochondrial localization in some cell types. While related family members PLD3/PLD4 have been shown to function as 5' exonucleases in endolysosomes rather than lipases, no enzymatic activity has been demonstrated for PLD5. The molecular function of PLD5 remains undefined - it may act as a pseudoenzyme/scaffold, have an unknown substrate, or possess a non-catalytic regulatory role. Overexpression in prostate cancer promotes proliferation and is regulated by miR-145-5p. PLD5 is distinct from PLD6/MitoPLD which has cardiolipin hydrolase activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | REMOVE | Summary: This annotation is based on InterPro domain IPR001736 (PLipase_D/transphosphatidylase) which is present in PLD5. However, authoritative reviews and UniProt explicitly state that PLD5 lacks the conserved HKD active sites and is catalytically inactive. Reason: PLD5 is explicitly designated as "Inactive phospholipase D5" by UniProt due to degenerate HKD catalytic motifs. Multiple reviews confirm PLD5 lacks phospholipase activity. Nelson and Frohman (2015) state PLD5 has "no catalytic activity" as a lipase. Bozatzi and Sapkota (2018) confirm PLD5 is "catalytically inactive" due to lacking HKD motifs. A 2023 structural analysis states "Little is known about PLD5, and it is even unclear if it is active as an enzyme." While the protein contains the PLD domain architecture, this IEA annotation incorrectly implies active catalytic function. The presence of a catalytic domain does not guarantee enzymatic activity - many pseudoenzymes exist. Supporting Evidence: file:human/PLD5/PLD5-uniprot.txt In contrast to other members of the family, it lacks the conserved active sites, suggesting that it has no phospholipase activity. file:human/PLD5/PLD5-deep-research-falcon.md PLD5 catalytic status: Authoritative reviews consistently report that human PLD5 lacks catalytic activity as a lipase because it lacks the requisite conserved HKD catalytic motifs; thus PLD5 is considered catalytically inactive within the classical PLD reaction framework file:human/PLD5/PLD5-deep-research-openai.md PLD5 is often referred to as an "inactive phospholipase D5" in databases |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: PLD5 is a single-pass type II transmembrane protein with a predicted transmembrane helix at residues 69-89. UniProt confirms membrane localization, and HPA data suggests mitochondrial membrane localization. Reason: While the general membrane annotation is correct, more specific localization data is available. Human Protein Atlas immunofluorescence data shows PLD5 is primarily localized to mitochondria in U-2 OS and A-549 cell lines. The protein has a single transmembrane domain consistent with a type II membrane topology. More specific annotations for intracellular membrane or mitochondrial membrane would be more informative. Proposed replacements: mitochondrial membrane Supporting Evidence: file:human/PLD5/PLD5-uniprot.txt SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass membrane protein {ECO:0000305}. file:human/PLD5/PLD5-deep-research-openai.md Data from the Human Protein Atlas indicate PLD5 is primarily localized to mitochondria in cultured human cells |
| GO:0003674 molecular_function | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: file:human/PLD5/PLD5-uniprot.txt In contrast to other members of the family, it lacks the conserved active sites, suggesting that it has no phospholipase activity. file:human/PLD5/PLD5-deep-research-openai.md Little is known about PLD5, and it is even unclear if it is active as an enzyme |
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Download this section (compressed HTML)Q: Does PLD5 have any enzymatic activity (e.g., nuclease activity like PLD3/PLD4, or other non-phospholipase activity)?
Q: What is the functional significance of PLD5 mitochondrial localization?
Q: Does PLD5 function as a pseudoenzyme/scaffold by binding substrates or regulators without catalyzing reactions?
Q: What are the binding partners of PLD5?
Q: Why is PLD5 expression enriched in brain/choroid plexus?
Experiment: In vitro biochemical assays testing PLD5 for nuclease activity (as seen in PLD3/PLD4) and other potential enzymatic activities
Hypothesis: PLD5 may have nuclease activity similar to its paralogs PLD3/PLD4
Type: biochemical assay
Experiment: Co-immunoprecipitation followed by mass spectrometry to identify PLD5 protein interaction partners
Hypothesis: PLD5 may function as a scaffold by interacting with other proteins
Type: proteomics
Experiment: CRISPR knockout of PLD5 in neuronal or choroid plexus cell lines to assess phenotypes
Hypothesis: Loss of PLD5 may reveal its function in brain-enriched tissues
Type: functional genomics
Experiment: Structural studies (X-ray crystallography or cryo-EM) to determine if PLD5 active site can accommodate substrates
Hypothesis: Structural analysis may reveal whether PLD5 can bind substrates despite lacking catalytic activity
Type: structural biology
Experiment: Submitochondrial fractionation to determine precise membrane localization (outer vs inner mitochondrial membrane)
Hypothesis: Precise localization may suggest functional context
Type: cell biology
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