Disease relevance of PLCD1

• Radioimmunoassay and immunoblot analysis revealed that in contrast to little difference in PLC-beta 1 and PLC-delta 1 content, a considerably higher level of PLC-gamma 1 was detected in 3 of 4 cases for adenoma and in all cases for carcinoma as compared to normal mucosa [1].
• On the other hand, decreased levels of the PLC delta 1 protein were seen in most colon carcinomas (12 of 13 paired samples) [2].
• Expression, purification and characterisation of a functional phosphatidylinositol-specific phospholipase C-delta 1 protein in Escherichia coli [3].
• Abnormal accumulation of phospholipase C-delta in filamentous inclusions of human neurodegenerative diseases [4].
• We found that the anti-PLC-delta antibody stained neuronal inclusions of Pick's disease, progressive supranuclear palsy and diffuse Lewy body disease while the inclusions of idiopathic Parkinson's disease lacked PLC-delta accumulation [4].

Psychiatry related information on PLCD1

• Alteration of phospholipase C-delta protein level and specific activity in Alzheimer's disease [5].

High impact information on PLCD1

• Here we discuss how the family of PLCs elaborates a minimal catalytic core typified by PLC-delta to confer multiple modes of regulation on their phospholipase activities [6].
• The best characterized of the intranuclear lipids are the inositol lipids that form the components of a phosphoinositide-phospholipase C cycle [7].
• Also, Galphaq(GTP[gammaS]) failed to associate with the C2 domain of PLC-delta, an isozyme that is not activated by Galphaq [8].
• G16 alpha did not activate PLC-gamma 1 or PLC-delta 1 [9].
• Also, the peptide was able to inhibit PI(4,5)P2 and G beta gamma activation of the PH-PLC delta 1 PH-PLC beta 2 enzymes in a concentration-dependent manner, suggesting that this is the region responsible for PH domain-mediated activation of the catalytic core [10].

Chemical compound and disease context of PLCD1

• We have previously demonstrated that an antibody to phosphoinositide-specific phospholipase C (PLC) isozyme, PLC-delta, intensely stained neurofibrillary tangles (NFT) in the brain tissue of Alzheimer's disease (AD) [4].

Biological context of PLCD1

• Because these and previous results indicate a common site of contact between the PH and catalytic domains in these two enzymes, we computationally docked the known structures of the PH and catalytic domains of PLC delta 1 [10].
• In vitro single point mutagenesis, inositol phospholipid hydrolysis, and substrate protection experiments were used to identify catalytic residues of human phosphatidylinositide-specific phospholipase C delta 1 (PLC delta 1) isolated from a human aorta cDNA library [11].
• We report here a missense mutation in the region encoding the C-terminal PH domain of the human PLC-delta 1 [12].
• In contrast GTP[S]-stimulated hydrolysis by phospholipase C-delta was not inhibited by any of the G-protein antibodies [13].
• Mutations within a highly conserved sequence present in the X region of phosphoinositide-specific phospholipase C-delta 1 [14].

Anatomical context of PLCD1

• PLD and PI-PLC activities in these four transfected cell lines as well as in nontransfected cells were measured by the formation of [3H]phosphatidylethanol [( 3H]PEt) and [3H]inositol phosphates [( 3H]IP) after labeling cellular phospholipids with [3H]oleic acid and [3H]inositol [15].
• Immunostaining of a specific antibody against the PLC isozyme, PLC-delta, demonstrated that this enzyme was abnormally accumulated in neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores, and neuropil threads in AD brains [16].
• The activity of PLC-delta 1 in the aortas of 12-week-old SHR is significantly higher at low Ca2+ concentration than that of normotensive WKY [17].
• Our PI-(4,5)P2 binding results support the hypothesis that the intact PH domain, serving as a specific tether, directs PLC-delta 1 to membranes enriched in PI(4,5)P2 and permits the active site, located elsewhere in the protein, to hydrolyze multiple substrate molecules before this enzyme dissociates from the membrane surface [18].
• In erythrocytes, activation of the phosphoinositide phospholipase C (PLC) or a 20 h ATP depletion, which both led to a reduction in the PIP2 content by 40-60%, did not affect Ca(2+)-induced phospholipid scrambling [19].

Associations of PLCD1 with chemical compounds

• This activation was almost completely blocked using neomycin (2.5mM), an inhibitor of phosphoinositide-phospholipase C (PI-PLC), Ro 318220 (1muM), a protein kinase C (PKC) inhibitor, and PP1 (50muM), a potent and selective inhibitor of the Src-family tyrosine kinases [20].
• PLC beta 2 can be activated by G beta gamma subunits, whereas PLC delta 1 can be activated by phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) [10].
• Mammalian inositol-specific phospholipase C-beta2 (PLC beta 2) and PLC delta 1 differ in their cellular activators [10].
• Phospholipid vesicle binding experiments showed that these three cleavage-defective mutant forms of PLC delta 1 could specifically bind to phosphatidylinositol 4,5-bisphosphate (PIP2) with an affinity similar to that of wild type enzyme [11].
• One of the delta-type isoforms, PLC-delta 1, binds to both phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) with a high affinity via its pleckstrin homology (PH) domain [12].

Physical interactions of PLCD1

• The PH delta PLC beta chimera showed PI(4,5)P2-dependent membrane binding similar to PLC delta 1 and a G beta gamma interaction energy close to that of PLC delta 1 [10].

Regulatory relationships of PLCD1

• The activity of PLC delta 3 was stimulated by polyamines and by basic proteins such as protamine, histone and mellitin [21].

Other interactions of PLCD1

• Mutation in the pleckstrin homology domain of the human phospholipase C-delta 1 gene is associated with loss of function [12].
• PLC-delta 1 was present in the cytoplasm of the bronchiolar epithelium whereas PLC-beta 1 was localized to the apical membranous portion of the same epithelium [22].
• This alignment predicts that C2 domains form two distinct topological folds, illustrated by the recent crystal structures of C2 domains from synaptotagmin 1 and phosphoinositide-specific phospholipase C-delta 1, respectively [23].
• Inositol-lipid-specific phospholipase C-delta 1 (PtdIns-PLC delta 1) was expressed in Escherichia coli as a fusion protein containing a short 22-amino-acid lac-Z-derived amino terminus [3].
• The order of amount present in the lung tissue was PLC-delta 1 > gamma 1 > beta 1 >> beta 3, in descending order [22].

Analytical, diagnostic and therapeutic context of PLCD1

• Western blot analysis confirmed that PLC-delta was concentrated in the paired helical filament (PHF)-rich fraction of AD brains [16].
• Molecular cloning, splice variants, expression, and purification of phospholipase C-delta 4 [24].
• To understand the mechanisms by which the C2 domain mediates the membrane targeting of PLC-delta isoforms, we measured the in vitro membrane binding of the C2 domains of PLC-delta1, -delta3, and -delta4 by surface plasmon resonance and monolayer techniques and their subcellular localization by time-lapse confocal microscopy [25].
• The role of residues contained within a highly conserved sequence present in the X region was investigated by site-directed mutagenesis of PLC-delta 1 isoenzyme [14].
• Only weak expression of PLC beta 1 was detected in these cell lines, by both western and northern blot analyses, and PLC delta 1 protein was not detected in any of the carcinoma cell lines [2].

References