PLA2G6

85 kDa calcium-independent phospholipase A2, also known as 85/88 kDa calcium-independent phospholipase A2, Group VI phospholipase A2, Intracellular membrane-associated calcium-independent phospholipase A2 beta, or Patatin-like phospholipase domain-containing protein 9 is an enzyme that in humans is encoded by the PLA2G6 gene.[5][6][7][8][9][10]

PLA2G6
Identifiers
AliasesPLA2G6, CaI-PLA2, GVI, INAD1, IPLA2-VIA, NBIA2, NBIA2A, NBIA2B, PARK14, PLA2, PNPLA9, iPLA2, iPLA2beta, phospholipase A2 group VI
External IDsOMIM: 603604 MGI: 1859152 HomoloGene: 2635 GeneCards: PLA2G6
Gene location (Human)
Chr.Chromosome 22 (human)[1]
Band22q13.1Start38,111,495 bp[1]
End38,214,778 bp[1]
RNA expression pattern




More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

8398

53357

Ensembl

ENSG00000184381

ENSMUSG00000042632

UniProt

O60733

P97819

RefSeq (mRNA)

NM_001199023
NM_001199024
NM_001199025
NM_016915

RefSeq (protein)

NP_001185952
NP_001185953
NP_001185954
NP_058611

Location (UCSC)Chr 22: 38.11 – 38.21 MbChr 15: 79.29 – 79.33 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

The PLA2G6 gene is located on the p arm of chromosome 22 at position 13.1 and it spans 80,605 base pairs.[8] The PLA2G6 gene produces an 18.6 kDa protein composed of 166 amino acids.[11][12] The resulting protein's structure has been shown to contain a lipase motif and 8 ankyrin repeats.[5] Different from rodent PLA2G6, which is known to share 90% overall amino acid sequence identity with that of the humans, the human PLA2G6 protein contains a 54-residue insertion which codes for a proline-rich region. This insertion has been shown to disrupt the last putative ankyrin repeat, as well as function as a linker region that segregates the N-terminal protein-binding domain from the C-terminal catalytic domain.[5][13]

Function

The PLA2G6 gene encodes for a phospholipase A2 enzyme, which is a subclass of enzyme that catalyzes the release of fatty acids from phospholipids.[8] This type of enzyme is responsible for breaking down (metabolizing) phospholipids. Phospholipid metabolism is essential for many body processes, including helping to maintain the integrity of the cell membrane.

Specifically, the A2 phospholipase produced from the PLA2G6 gene, sometimes called PLA2 group VI, helps to regulate the levels of a compound called phosphatidylcholine, which is abundant in the cell membrane.[14] The encoded protein may also play a role in phospholipid remodelling, arachidonic acid release, nitric oxide-induced or vasopressin-induced arachidonic acid release and in leukotriene and prostaglandin synthesis, Fas receptor-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells.[8][9]

It addition, it has a role in cardiolipin (CL) deacylation, and is required for both speed and directionality of monocyte MCP1/CCL2-induced chemotaxis through regulation of F-actin polymerization at the pseudopods. Isoform ankyrin-iPLA2-1 and isoform ankyrin-iPLA2-2, which lack the catalytic domain, are probably involved in the negative regulation of PLA2G6 activity.[9] Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only two of them have been determined to date.[8]

Catalytic activity

Phosphatidylcholine + H2O = 1-acylglycerophosphocholine + a carboxylate.[10][9]

Model organisms

Model organisms have been used in the study of PLA2G6 function. A conditional knockout mouse line called Pla2g6tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[15] Male and female animals underwent a standardized phenotypic screen[16] to determine the effects of deletion.[17][18][19][20] Additional screens performed: - In-depth immunological phenotyping.[21]

Clinical significance

Mutations in PLA2G6 has been shown to result in mitochondrial deficiencies and associated disorders, including Neurodegeneration with brain iron accumulation 2B (NBIA2B), Neurodegeneration with brain iron accumulation 2A (NBIA2A), Parkinson disease 14 (PARK14), and hereditary spastic paraplegia.[22][9][10]

Neurodegeneration with brain iron accumulation 2B (NBIA2B)

Neurodegeneration with brain iron accumulation 2B (NBIA2B) is a neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. It is characterized by progressive extrapyramidal dysfunction leading to rigidity, dystonia, dysarthria and sensorimotor impairment.[9][10]

Neurodegeneration|Neurodegeneration with brain iron accumulation 2A (NBIA2A)

Neurodegeneration with brain iron accumulation 2A (NBIA2A) is a neurodegenerative disease characterized by pathologic axonal swelling and spheroid bodies in the central nervous system. Onset is within the first 2 years of life with death by age 10 years.[9][10]

Parkinson disease 14 (PARK14)

Parkinson disease 14 (PARK14) is an adult-onset progressive neurodegenerative disorder characterized by parkinsonism, dystonia, severe cognitive decline, cerebral and cerebellar atrophy and absent iron in the basal ganglia on magnetic resonance imaging.[9][10]

Hereditary spastic paraplegia

Hereditary spastic paraplegias are a diverse class of hereditary degenerative spinal cord disorders characterized by a slow, gradual, progressive weakness and spasticity (stiffness) of the legs. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. Rate of progression and the severity of symptoms are quite variable.[23]

Another disease associated with mutations in this gene is infantile neuroaxonal dystrophy.

Interactions

PLA2G6 has been shown to have Protein-protein interactions with the following.[24][9]

References

  1. GRCh38: Ensembl release 89: ENSG00000184381 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000042632 - 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.
  5. Larsson PK, Claesson HE, Kennedy BP (Jan 1998). "Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity". The Journal of Biological Chemistry. 273 (1): 207–14. doi:10.1074/jbc.273.1.207. PMID 9417066.
  6. Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ (Sep 2006). "Characterization of the human patatin-like phospholipase family". Journal of Lipid Research. 47 (9): 1940–9. doi:10.1194/jlr.M600185-JLR200. PMID 16799181.
  7. Kienesberger PC, Oberer M, Lass A, Zechner R (Apr 2009). "Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions". Journal of Lipid Research. 50 Suppl: S63–8. doi:10.1194/jlr.R800082-JLR200. PMC 2674697. PMID 19029121.
  8. "Entrez Gene: PLA2G6 phospholipase A2, group VI (cytosolic, calcium-independent)". This article incorporates text from this source, which is in the public domain.
  9. "PLA2G6 - 85/88 kDa calcium-independent phospholipase A2 - Homo sapiens (Human) - PLA2G6 gene & protein". Retrieved 2018-08-22. This article incorporates text available under the CC BY 4.0 license.
  10. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  11. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  12. "85/88 kDa calcium-independent phospholipase A2". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  13. Ma Z, Wang X, Nowatzke W, Ramanadham S, Turk J (Apr 1999). "Human pancreatic islets express mRNA species encoding two distinct catalytically active isoforms of group VI phospholipase A2 (iPLA2) that arise from an exon-skipping mechanism of alternative splicing of the transcript from the iPLA2 gene on chromosome 22q13.1". The Journal of Biological Chemistry. 274 (14): 9607–16. doi:10.1074/jbc.274.14.9607. PMC 3715997. PMID 10092647.
  14. "PLA2G6". Genetics Home Reference. NCBI. This article incorporates text from this source, which is in the public domain.
  15. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  16. "International Mouse Phenotyping Consortium".
  17. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  18. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  19. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  20. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (Jul 2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
  21. "Infection and Immunity Immunophenotyping (3i) Consortium".
  22. Ozes B, Karagoz N, Schüle R, Rebelo A, Sobrido MJ, Harmuth F, Synofzik M, Pascual SIP, Colak M, Ciftci-Kavaklioglu B, Kara B, Ordóñez-Ugalde A, Quintáns B, Gonzalez MA, Soysal A, Zuchner S, Battaloglu E (2017) PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia. Clin Genet 92(5):534-539
  23. "Hereditary spastic paraplegia". www.uniprot.org.
  24. Mick DU, Dennerlein S, Wiese H, Reinhold R, Pacheu-Grau D, Lorenzi I, Sasarman F, Weraarpachai W, Shoubridge EA, Warscheid B, Rehling P (December 2012). "MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation". Cell. 151 (7): 1528–41. doi:10.1016/j.cell.2012.11.053. PMID 23260140.

Further reading

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.