Phospholipase D

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Phospholipase D
Identifiers
SymbolPLDc
SCOP2
1byr / SCOPe / SUPFAM
OPM superfamily118
OPM protein3rlh
CDDcd00138
Membranome306
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
phospholipase D
Identifiers
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

a phosphatidylcholine + H2O = choline + a phosphatidate

Phospholipases occur widely, and can be found in a wide range of organisms, including bacteria, yeast, plants, animals, and viruses.

membrane trafficking, cytoskeletal reorganization, receptor-mediated endocytosis, exocytosis, and cell migration.[6] Through these processes, it has been further implicated in the pathophysiology of multiple diseases: in particular the progression of Parkinson's and Alzheimer's, as well as various cancers.[4][6] PLD may also help set the threshold for sensitivity to anesthesia and mechanical force.[7][8]

Discovery

PLD-type

castor bean; PLDα was ultimately cloned and characterized from a variety of plants, including rice, corn, and tomato.[1] Plant PLDs have been cloned in three isoforms: PLDα, PLDβ, and PLDγ.[9]
More than half a century of biochemical studies have implicated phospholipase D and
oncogenesis.[10]

Function

Strictly speaking, phospholipase D is a

hydrolyze other phospholipid substrates, such as cardiolipin, or even the phosphodiester bond constituting the backbone of DNA.[5]

Phosphatidic acid

Main article: Phosphatidic acid

Many of phospholipase D's

vesicle trafficking, endocytosis, exocytosis, actin cytoskeleton dynamics, cell proliferation differentiation, and migration.[5]

phospholipids help recruit adaptor proteins (AP) and coat proteins (CP) to the membrane, initiating the budding of the vesicle. Vesicle fission is ultimately mediated by dynamin, which itself is a downstream effector
of PA.

TYK and controls the signalling indicating that PLD is activated by these kinases.[13] As choline
is very abundant in the cell, PLD activity does not significantly affect choline levels, and choline is unlikely to play any role in signalling.

signal molecule and acts to recruit SK1 to membranes. PA is extremely short lived and is rapidly hydrolysed by the enzyme phosphatidate phosphatase to form diacylglycerol (DAG). DAG may also be converted to PA by DAG kinase. Although PA and DAG are interconvertible, they do not act in the same pathways. Stimuli that activate PLD do not activate enzymes downstream
of DAG and vice versa.

It is possible that, though PA and DAG are interconvertible, separate pools of signalling and non-signalling

monounsaturated or saturated. Thus functional saturated/monounsaturated PA can be degraded by hydrolysing it to form non-functional saturated/monounsaturated DAG while functional polyunsaturated DAG can be degraded by converting it into non-functional polyunsaturated PA.[14][15][16]

A lysophospholipase D called autotaxin was recently identified as having an important role in cell-proliferation through its product, lysophosphatidic acid (LPA).

Structure

Plant and animal PLDs have a consistent

amino acids.[4][5] These two HKD motifs confer hydrolytic activity to PLD, and are critical for its enzymatic activity both in vitro and in vivo.[5][10] Hydrolysis of the phosphodiester bond occurs when these HKD sequences are in the correct proximity
.

Human proteins containing this motif include:

phosphatidylserine synthase, bacterial PLDs, and viral proteins. Each of these appears to possess a domain duplication which is apparent by the presence of two HKD motifs containing well-conserved histidine, lysine, and asparagine residues which may contribute to the active site aspartic acid. An Escherichia coli endonuclease (nuc) and similar proteins appear to be PLD homologues but possess only one of these motifs.[19][20][21][22]

PLD

genes additionally encode highly conserved regulatory domains: the phox consensus sequence (PX), the pleckstrin homology domain (PH), and a binding site for phosphatidylinositol 4,5-bisphosphate (PIP2).[2]

Mechanism of catalysis

PLD-

histidines form transient covalent bonds with the phospholipid, producing a short-lived intermediate that can be easily hydrolyzed by water in a subsequent step.[4][12]

Substrate presentation; PLD (blue oval) is sequestered into cholesterol-dependent lipid domains (green lipids) by palmitoylation. PLD also binds PIP2(red hexagon) domains (grey shading) located in the disordered region of the cell with phosphatidylcholine (PC). When PIP2 increases in the cell PLD translocates to PIP2 where it is exposed to and hydrolizes PC to phosphatidic acid (red spherical lipid).

Mechanism of activation

Substrate presentation For mammalian PLD2, the molecular basis of activation is substrate presentation. The enzyme resides inactive in lipid micro-domains rich in sphingomyelin and depleted of PC substrate.[23] Increased PIP2 or a decrease in cholesterol causes the enzyme to translocate to PIP2 micro domains near its substrate PC. Hence PLD can is primarily activated by localization within the plasma membrane rather than a protein conformational change. Disruption of lipid domains by anesthetics.[24] or mechanical force.[23] The protein may also undergo a conformational change upon PIP2 binding, but this has not been shown experimentally and would constitute a mechanism of activation distinct from substrate presentation.

Isoforms

Two major

Golgi complex.[10]

PLD1

Main article:
PLD1

plasma membrane. Basal PLD1 activity is low however, and in order to transduce the extracellular signal, it must first be activated by proteins such as Arf, Rho, Rac, and protein kinase C.[5][6][11]

Chr. 3 q26
Search for
StructuresSwiss-model
DomainsInterPro

PLD2

Main article: PLD2

In contrast, PLD2 is a 106

lipid rafts.[4][6] It has high intrinsic catalytic activity, and is only weakly activated by the above molecules.[4]
Chr. 17 p13.3
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StructuresSwiss-model
DomainsInterPro

Regulation

The activity of phospholipase D is extensively

secondary messenger.[4]

Specific

extracellular signals.[4]

C2 domain

Main article: C2 domain

substrate by strengthening the binding of the activator PIP2.[4]

PX domain

Main article: PX domain

The

plasma membrane.[1]

PH domain

Main article:
PH domain

The highly conserved

lipid rafts.[1]

Interactions with small GTPases

Main article: Small GTPase

In

plasma membrane is essential for PLD activation.[1][4]

Physiological and pathophysiological roles

Alcohol Intoxication

Phospholipase D metabolizes ethanol into phosphatidylethanol (PEtOH) in a process termed transphosphatidylation. Using fly genetics the PEtOH was shown to mediates alcohol's hyperactive response in fruit flies.[27] And ethanol transphosphatidylation was shown to be up-regulated in alcoholics and the family members of alcoholic.s[28] This ethanol transphosphatidylation mechanism recently emerged as an alternative theory for alcohol's effect on ion channels. Many ion channels are regulated by anionic lipids.[29] and the competition of PEtOH with endogenous signaling lipids is thought to mediate the effect of ethanol on ion channels in some instances and not direct binding of the free ethanol to the channel.[27]

Mechanosensation

PLD2 is a mechanosensor and directly sensitive to mechanical disruption of clustered GM1 lipids.[3] Mechanical disruption (fluid shear) then signals for the cell to differentiate. PLD2 also activates TREK-1 channels, a potassium channel in the analgesic pathway.[30]

In cancer

Phospholipase D is a regulator of several critical cellular processes, including

renal cancer.[5][6] However, the molecular pathways through which PLD drives cancer progression remain unclear.[5] One potential hypothesis casts a critical role for phospholipase D in the activation of mTOR, a suppressor of cancer cell apoptosis.[5] The ability of PLD to suppress apoptosis in cells with elevated tyrosine kinase activity makes it a candidate oncogene in cancers where such expression is typical.[6]

In neurodegenerative diseases

Phospholipase D may also play an important

Lewy bodies, protein aggregates that are the hallmarks of Parkinson's disease.[5] Disinhibition of PLD by α-synuclein may contribute to Parkinson's deleterious phenotype.[5]

Abnormal PLD activity has also been suspected in

superfamily, has also been associated with the pathogenesis of this disease.[31]

Gallery

  • Phosphatidyl choline
    Phosphatidyl choline
  • Phosphatidate
    Phosphatidate
  • Choline
    Choline
  • Phospholipase cleavage sites
    Phospholipase cleavage sites

References

  1. ^
    S2CID 26447185
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  2. ^
    PMID 11987824
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  3. ^
    PMID 27976674
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  4. ^
    S2CID 14815405
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  5. ^
    PMID 21447092
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  6. ^
    PMID 14517341
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  7. doi:10.1101/758896
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  8. PMID 32467161
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  9. ^
    S2CID 24389113
    .
  10. ^
    PMID 15052340
    .
  11. ^
    PMID 8144636
    .
  12. ^
    PMID 10873862
    .
  13. S2CID 28348537
    .
  14. PMID 3117799
    .
  15. S2CID 10674790
    .
  16. PMID 9644971
    .
  17. S2CID 21937549
    .
  18. ^ Nowicki M (2006). Characterization of the Cardiolipin Synthase from Arabidopsis thaliana (Ph.D. thesis). RWTH-Aachen University. Archived from the original on 2011-10-05. Retrieved 2011-07-11.
  19. PMID 8732763
    .
  20. PMID 8755242
    .
  21. PMID 8051126
    .
  22. PMID 9242915
    .
  23. ^
    PMID 27976674
    .
  24. PMID 32467161
    .
  25. ^
    PMID 22157867
    .
  26. PMID 27976674
    .
  27. ^
    PMID 30529033
    .
  28. PMID 3200856
    .
  29. PMID 25633344
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  30. PMID 25197053
    .
  31. PMID 24336208
    .

External links
This article incorporates text from the public domain Pfam and InterPro: IPR001734
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