PLCE1

PLCE1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2BYE, 2BYF, 2C5L
Identifiers
Aliases	PLCE1 , NPHS3, PLCE, PPLC, phospholipase C epsilon 1
External IDs	OMIM: 608414 MGI: 1921305 HomoloGene: 9478 GeneCards: PLCE1
Gene location (Human)
Chr.	Chromosome 10 (human)
End	94,332,823 bp
Gene location (Mouse)
Chr.	Chromosome 19 (mouse)
End	38,785,030 bp
RNA expression pattern
	; ;
	More reference expression data
Gene ontology
Molecular function	• guanyl-nucleotide exchange factor activity ; • signal transducer activity ; • GO:0001948 protein binding ; • phosphoric diester hydrolase activity ; • enzyme binding ; • phospholipase C activity ; • hydrolase activity ; • phosphatidylinositol phospholipase C activity ; • metal ion binding ;
Cellular component	• cytosol ; • Golgi apparatus ; • membrane ; • Golgi membrane ; • plasma membrane ; • cytoplasm ;
Biological process	• GO:0007243 intracellular signal transduction ; • epidermal growth factor receptor signaling pathway ; • regulation of G protein-coupled receptor signaling pathway ; • regulation of smooth muscle contraction ; • lipid metabolism ; • positive regulation of cytosolic calcium ion concentration ; • small GTPase mediated signal transduction ; • regulation of Ras protein signal transduction ; • glomerulus development ; • inositol phosphate metabolic process ; • diacylglycerol biosynthetic process ; • lipid catabolic process ; • phospholipase C-activating G protein-coupled receptor signaling pathway ; • heart development ; • cytoskeleton organization ; • regulation of cell growth ; • regulation of protein kinase activity ; • cell population proliferation ; • inositol phosphate-mediated signaling ; • calcium-mediated signaling ; • signal transduction ; • Ras protein signal transduction ; • inositol trisphosphate biosynthetic process ; • phosphatidylinositol-mediated signaling ; • release of sequestered calcium ion into cytosol ;
	Sources:Amigo / QuickGO
Orthologs
	51196
	74055
	ENSG00000138193
	ENSMUSG00000024998
	Q9P212
	Q8K4S1
	NM_001165979 ; NM_001288989 ; NM_016341
	NM_019588
	NP_001159451 ; NP_001275918 ; NP_057425
	NP_062534
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated September 13, 2021

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1) is an enzyme that in humans is encoded by the PLCE1 gene.^[5]^[6] This gene encodes a phospholipase enzyme (PLCE1) that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Mutations in this gene cause early-onset nephrotic syndrome and have been associated with respiratory chain deficiency with diffuse mesangial sclerosis.^[7]^[8]

Structure

PLCE1 is located on the q arm of chromosome 10 in position 23.33 and has 39 exons.^[7] PLCE1, the protein encoded by this gene, is located on the Golgi apparatus, the cell membrane, and in the cytosol. It contains 3 turns, 15 beta strands, and 6 alpha helixes. PLCE1 contains a 260 amino acid Ras-GEF domain at p. 531-790, a 149 amino acid PI-PLC X-box domain at p. 1392-1540, a 117 amino acid PI-PLC Y-box domain at p. 1730 – 1846, a 101 amino acid C2 domain at p. 1856 – 1956, a 103 amino acid Ras-associating 1 domain at p. 2012 – 2114, and a 104 amino acid Ras-associating 2 domain at p. 2135 – 2238. There is a region of 79 amino acids from p. 1686 – 1764 that is required for PLCE1 to be activated by RHOA, RHOB, GNA12, GNA13 and G-beta gamma. PLCE1 also has a Ca2+ cofactor.^[6]^[9]^[10] Alternative splicing results in multiple transcript variants encoding distinct isoforms.^[7]

Function

PLCE1 belongs to the phospholipase family that catalyzes the hydrolysis of polyphosphoinositides such as phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to generate the second messengers Ins(1,4,5)P3 and diacylglycerol. These products initiate a cascade of intracellular responses that result in cell growth and differentiation and gene expression.[supplied by OMIM]^[7]

Catalytic activity

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O = 1D-myo-inositol 1,4,5-trisphosphate + diacylglycerol.^[5]^[6]

Clinical significance

Mutations in this gene cause early-onset nephrotic syndrome. This disease is characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis.^[7] Signs and symptoms include kidney biopsies demonstrating non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation as well as genetic tests revealing a pathogenic S1484L mutation. Diffuse mesangial proliferation is characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen.^[11]^[9]^[10] This disease has also been associated with mitochondrial cytopathy stemming from respiratory chain deficiency primarily affecting complex IV.^[8]

Additionally, Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and it has been found that this protein is over expressed during heart failure. Research has suggested that PLCE1 may thus inhibit cardiac hypertrophy.^[12]^[9]^[10]

Interactions

PLCE1 has been shown to have 12 binary protein-protein interactions including 8 co-complex interactions. PLCE1 appears to interact with RyR2, HRAS, NRAS, and LIMS1.^[13]

Related Research Articles

Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP₃ or Ins3P or IP₃ is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂), a phospholipid that is located in the plasma membrane, by phospholipase C (PLC). Together with diacylglycerol (DAG), IP₃ is a second messenger molecule used in signal transduction in biological cells. While DAG stays inside the membrane, IP₃ is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. When IP₃ binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.

Phosphoinositide phospholipase C (PLC) is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. These enzymes belong to a larger superfamily of Phospholipase C. Other families of phospholipase C enzymes have been identified in bacteria and trypanosomes. Phospholipases C are phosphodiesterases.

Phosphatidylinositol 4,5-bisphosphate Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P₂, also known simply as PIP₂ or PI(4,5)P₂, is a minor phospholipid component of cell membranes. PtdIns(4,5)P₂ is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins.

Phospholipase D (PLD) is an enzyme of the phospholipase superfamily. Phospholipases occur widely, and can be found in a wide range of organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase D's principal substrate is phosphatidylcholine, which it hydrolyzes to produce the signal molecule phosphatidic acid (PA), and soluble choline in a cholesterol dependent process called substrate presentation. Plants contain numerous genes that encode various PLD isoenzymes, with molecular weights ranging from 90 to 125 kDa. Mammalian cells encode two isoforms of phospholipase D: PLD1 and PLD2. Phospholipase D is an important player in many physiological processes, including membrane trafficking, cytoskeletal reorganization, receptor-mediated endocytosis, exocytosis, and cell migration. 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. PLD may also help set the threshold for sensitivity to anesthesia and mechanical force.

G_q protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the G_q/11 (G_q/G₁₁) family or G_q/11/14/15 family to include closely related family members. G alpha subunits may be referred to as G_q alpha, G_αq, or G_qα. G_q proteins couple to G protein-coupled receptors to activate beta-type phospholipase C (PLC-β) enzymes. PLC-β in turn hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) to diacyl glycerol (DAG) and inositol trisphosphate (IP₃). IP₃ acts as a second messenger to release stored calcium into the cytoplasm, while DAG acts as a second messenger that activates protein kinase C (PKC).

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the PLCG2 gene.

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP₂) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃), which serve as second messengers. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca²⁺, and phospholipids.

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-1 is an enzyme that in humans is encoded by the PLCB1 gene.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta isoform is an enzyme that in humans is encoded by the PIK3CB gene.

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-2 is an enzyme that in humans is encoded by the PLCB2 gene.

Serine/threonine-protein kinase D3 (PKD3) or PKC-nu is an enzyme that in humans is encoded by the PRKD3 gene.

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-3 is an enzyme that in humans is encoded by the PLCB3 gene.

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-1 is an enzyme that in humans is encoded by the PLCD1 gene. PLCd1 is essential to maintain homeostasis of the skin.

Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha polypeptide is an enzyme that in humans is encoded by the PIK3C2A gene.

Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing beta polypeptide is an enzyme that in humans is encoded by the PIK3C2B gene.

Glutamate [NMDA] receptor subunit epsilon-3 is a protein that in humans is encoded by the GRIN2C gene.

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-3 is an enzyme that in humans is encoded by the PLCD3 gene.

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-4 is an enzyme that in humans is encoded by the PLCD4 gene.

1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-4 is an enzyme that in humans is encoded by the PLCB4 gene.

In molecular biology, Tat is a protein that is encoded for by the tat gene in HIV-1. Tat is a regulatory protein that drastically enhances the efficiency of viral transcription. Tat stands for "Trans-Activator of Transcription". The protein consists of between 86 and 101 amino acids depending on the subtype. Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000138193 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024998 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
1 2 Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW (January 2001). "A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogen-activated protein kinase pathway". The Journal of Biological Chemistry. 276 (4): 2758–65. doi: 10.1074/jbc.M008119200 . PMID 11022047.
1 2 3 Song C, Hu CD, Masago M, Kariyai K, Yamawaki-Kataoka Y, Shibatohge M, Wu D, Satoh T, Kataoka T (January 2001). "Regulation of a novel human phospholipase C, PLCepsilon, through membrane targeting by Ras". The Journal of Biological Chemistry. 276 (4): 2752–7. doi: 10.1074/jbc.M008324200 . PMID 11022048.
1 2 3 4 5 "Entrez Gene: PLCE1 phospholipase C, epsilon 1".This article incorporates text from this source, which is in the public domain.
1 2 Baskin E, Selda Bayrakci U, Alehan F, Ozdemir H, Oner A, Horvath R, Vega-Warner V, Hildebrandt F, Ozaltin F (July 2011). "Respiratory-chain deficiency presenting as diffuse mesangial sclerosis with NPHS3 mutation". Pediatric Nephrology. 26 (7): 1157–61. doi:10.1007/s00467-011-1814-0. PMC 3329966 . PMID 21365190.
1 2 3 "PLCE1 - 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 - Homo sapiens (Human) - PLCE1 gene & protein". www.uniprot.org. Retrieved 2018-08-30. This article incorporates text available under the CC BY 4.0 license.
1 2 3 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571 . PMID 27899622.
↑ Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nürnberg G, et al. (December 2006). "Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible". Nature Genetics. 38 (12): 1397–405. doi:10.1038/ng1918. PMID 17086182. S2CID 4037950.
↑ Wang H, Oestreich EA, Maekawa N, Bullard TA, Vikstrom KL, Dirksen RT, Kelley GG, Blaxall BC, Smrcka AV (December 2005). "Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and inhibits cardiac hypertrophy". Circulation Research. 97 (12): 1305–13. doi: 10.1161/01.RES.0000196578.15385.bb . PMID 16293787.
↑ IntAct. www.ebi.ac.uk https://www.ebi.ac.uk/intact/interactions?conversationContext=1 . Retrieved 2018-08-30.Missing or empty |title= (help)

Jefferson JA, Shankland SJ (July 2007). "Familial nephrotic syndrome: PLCE1 enters the fray". Nephrology, Dialysis, Transplantation. 22 (7): 1849–52. doi: 10.1093/ndt/gfm098 . PMID 17449496.
Cefai D, Debre P, Kaczorek M, Idziorek T, Autran B, Bismuth G (December 1990). "Human immunodeficiency virus-1 glycoproteins gp120 and gp160 specifically inhibit the CD3/T cell-antigen receptor phosphoinositide transduction pathway". The Journal of Clinical Investigation. 86 (6): 2117–24. doi:10.1172/JCI114950. PMC 329852 . PMID 1979339.
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Mayne M, Bratanich AC, Chen P, Rana F, Nath A, Power C (1998). "HIV-1 tat molecular diversity and induction of TNF-alpha: implications for HIV-induced neurological disease". Neuroimmunomodulation. 5 (3–4): 184–92. doi:10.1159/000026336. PMID 9730685. S2CID 19529677.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000138193 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024998 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid11022047-5] 1 2 Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW (January 2001). "A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogen-activated protein kinase pathway". The Journal of Biological Chemistry. 276 (4): 2758–65. doi: 10.1074/jbc.M008119200 . PMID 11022047.

[pmid11022048-6] 1 2 3 Song C, Hu CD, Masago M, Kariyai K, Yamawaki-Kataoka Y, Shibatohge M, Wu D, Satoh T, Kataoka T (January 2001). "Regulation of a novel human phospholipase C, PLCepsilon, through membrane targeting by Ras". The Journal of Biological Chemistry. 276 (4): 2752–7. doi: 10.1074/jbc.M008324200 . PMID 11022048.

[entrez2-7] 1 2 3 4 5 "Entrez Gene: PLCE1 phospholipase C, epsilon 1".This article incorporates text from this source, which is in the public domain.

[:1-8] 1 2 Baskin E, Selda Bayrakci U, Alehan F, Ozdemir H, Oner A, Horvath R, Vega-Warner V, Hildebrandt F, Ozaltin F (July 2011). "Respiratory-chain deficiency presenting as diffuse mesangial sclerosis with NPHS3 mutation". Pediatric Nephrology. 26 (7): 1157–61. doi:10.1007/s00467-011-1814-0. PMC 3329966 . PMID 21365190.

[:2-9] 1 2 3 "PLCE1 - 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 - Homo sapiens (Human) - PLCE1 gene & protein". www.uniprot.org. Retrieved 2018-08-30. This article incorporates text available under the CC BY 4.0 license.

[:0-10] 1 2 3 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571 . PMID 27899622.

[11] Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nürnberg G, et al. (December 2006). "Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible". Nature Genetics. 38 (12): 1397–405. doi:10.1038/ng1918. PMID 17086182. S2CID 4037950.

[12] Wang H, Oestreich EA, Maekawa N, Bullard TA, Vikstrom KL, Dirksen RT, Kelley GG, Blaxall BC, Smrcka AV (December 2005). "Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and inhibits cardiac hypertrophy". Circulation Research. 97 (12): 1305–13. doi: 10.1161/01.RES.0000196578.15385.bb . PMID 16293787.

[13] IntAct. www.ebi.ac.uk https://www.ebi.ac.uk/intact/interactions?conversationContext=1 . Retrieved 2018-08-30.Missing or empty |title= (help)

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v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)