Phospholipase D1

PLD1
Identifiers
Aliases	PLD1, phospholipase D1, CVDD
External IDs	OMIM: 602382; MGI: 109585; HomoloGene: 116234; GeneCards: PLD1; OMA:PLD1 - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q26.31 Start 171,600,404 bp[1] End 171,810,950 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 A3|3 11.15 cM Start 27,992,844 bp[2] End 28,187,511 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gallbladder right adrenal cortex mucosa of esophagus duodenum left adrenal gland corpus callosum left adrenal cortex skin of abdomen skin of leg jejunal mucosa Top expressed in zygote secondary oocyte primary oocyte crypt of lieberkuhn of small intestine jejunum ileum left colon vestibular membrane of cochlear duct epithelium of lens Paneth cell More reference expression data BioGPS More reference expression data
Gene ontology Molecular function phospholipase D activity N-acylphosphatidylethanolamine-specific phospholipase D activity protein binding catalytic activity phosphatidylinositol binding hydrolase activity Cellular component cytoplasm late endosome membrane Golgi membrane endocytic vesicle lysosomal membrane apical plasma membrane endoplasmic reticulum perinuclear region of cytoplasm endosome endoplasmic reticulum membrane membrane Golgi apparatus plasma membrane specific granule membrane tertiary granule membrane cholinergic synapse Biological process regulation of microvillus assembly lipid metabolism cell motility small GTPase mediated signal transduction lipid catabolic process chemotaxis Ras protein signal transduction neutrophil degranulation phosphatidic acid biosynthetic process inositol lipid-mediated signaling regulation of synaptic vesicle cycle Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5337 18805 Ensembl ENSG00000075651 ENSMUSG00000027695 UniProt Q13393 Q9Z280 RefSeq (mRNA) NM_001130081 NM_002662 NM_001164056 NM_008875 NM_001368667 RefSeq (protein) NP_001123553 NP_002653 n/a Location (UCSC) Chr 3: 171.6 – 171.81 Mb Chr 3: 27.99 – 28.19 Mb PubMed search [3] [4]
Wikidata
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Phospholipase D₁ (PLD1) is an enzyme that in humans is encoded by the PLD1 gene,^[5][6] though analogues are found in plants, fungi, prokaryotes, and even viruses.^[7]

History

The possibility of PLD1 was first mentioned in 1947 by authors Hanahan and Chaikoff at Berkeley when describing a carrot enzyme that could "[split] choline from phospholipids."^[8] PLD was first derived in mammals in 1975 by Saito and Kanfer, who noted its activity in rats.^[9] PLD was first cloned from HeLa cell cDNA in 1995, while mammalian PLD1 was first cloned from a rat in 1997.^[7]

Function

Phosphatidylcholine (PC)-specific phospholipases D (PLDs) EC 3.1.4.4 catalyze the hydrolysis of PC to produce phosphatidic acid (PA) and choline. A range of agonists acting through G protein-coupled receptors and receptor tyrosine kinases stimulate this hydrolysis. PC-specific PLD activity has been implicated in numerous cellular pathways, including membrane trafficking, signal transduction, platelet coagulation, mitosis, apoptosis, and the creation of cytoplasmic lipid droplets.^{[6][7][10][11]}

Membrane trafficking

PLD1 has been shown to associate at the plasma membrane, late endosome,^[12] early endosome, and the Golgi apparatus.^[7][9] There is evidence that PA is able to assist in negative membrane curvature due to its head group being smaller than in many other lipids.^[7] One experiment with PLD1 knockout showed a significant reduction in the number of exocytotic fusion events, implying a strong role in exocytosis.^[13]

Signal transduction

PLD1 may play a role in some cells in the endocytosis of signaling receptors or exocytosis of signaling molecules. For example, one experiment in B cells showed that limiting PLD1 led to significantly reduced endocytosis of the B cell receptor.^[12] Another experiment showed that knocking out PLD1 may hinder the ability of mice to secrete catecholamines, molecules that are essential for vesicular communication across the body.^[13]

Structure

Mammalian PLD1 has several domains for activators, inhibitors, and catalysis, which it shares with PLD2. Domains for both activation and inhibition are referred to as the phox homology (PX) and pleckstrin homology (PH) domains. The catalytic domain consists of two HKD regions, so named for three of the amino acids that are key in catalysis. These domains are conserved across many organisms.^[7][9] There are two splice variants of the protein, PLD1a and PLD1b, but they do not seem to localize any differently.^[7]

Applications

Alzheimer's disease: PA, which is produced in part by PLD1, seems to be involved in the movement of β-amyloid, which could precede amyloidogenesis.^[14]

Cancer: certain rat tumors with dominant negative PLD do not appear to form new colonies or tumors.^[7][14]

Thrombosis: PLD knockout mice appear to have reduced occlusion, thus offsetting thrombosis.^[7]

Type II Diabetes: the protein PED/PEA15 is often elevated in type II diabetic patients, thus enhancing PLD1 activity, and in turn impairing insulin.^[7]

Interactions

Phospholipase D1 has been shown to interact with:

Inhibitors

• Calphostin-c, an inhibitor^[7]
• VU-0359595: 1,700-fold selective versus phospholipase D2, IC₅₀ = 3.7nM.^[24]

References

Further reading