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
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

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]

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]

Clinical significance

Mutations in PLA2G6 has been shown to result in mitochondrial deficiencies and associated disorders, including PLA2G6-associated neurodegeneration (PLAN), which has several subtypes and is also known as Neurodegeneration with brain iron accumulation type 2 (NBIA2), other forms of disease are also referred to as Parkinson disease 14 (PARK14), and hereditary spastic paraplegia.[15][9][10]

PLA2G6-associated neurodegeneration (PLAN)

PLA2G6-associated neurodegeneration (PLAN) 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][16]

Infantile neuroaxonal dystrophy (INAD)

The most severe form is called infantile neuroaxonal dystrophy (INAD), also Neurodegeneration with brain iron accumulation type 2A (NBIA2A), and is characterized by pathologic axonal swelling and spheroid bodies in the central nervous system. Onset is within the first 2 years of life with death often by the age of 10 years.[9][10][16]

Atypical neuroaxonal dystrophy (atypical NAD)

A later-childhood onset and more slowly progressive form is called atypical neuraxonal dystrophy (atypical NAD), also Neurodegeneration with brain iron accumulation type 2B (NBIA2B).[16]

An adult-onset disease called PLA2G6-related dystonia-parkinsonism develop dystonia and parkinsonism after earlier normal development, and is also caused by biallelic mutations to PLA2G6.[16]

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.[17]

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.[18][9]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000184381 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 Larsson PK, Claesson HE, Kennedy BP (January 1998). "Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity". The Journal of Biological Chemistry. 273 (1): 207–214. doi:10.1074/jbc.273.1.207. PMID 9417066.
  6. ↑ Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ (September 2006). "Characterization of the human patatin-like phospholipase family". Journal of Lipid Research. 47 (9): 1940–1949. doi:10.1194/jlr.M600185-JLR200. PMID 16799181.
  7. ↑ Kienesberger PC, Oberer M, Lass A, Zechner R (April 2009). "Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions". Journal of Lipid Research. 50 Suppl (Suppl): S63–S68. doi:10.1194/jlr.R800082-JLR200. PMC 2674697. PMID 19029121.
  8. 1 2 3 4 5 "Entrez Gene: PLA2G6 phospholipase A2, group VI (cytosolic, calcium-independent)".Public Domain This article incorporates text from this source, which is in the public domain.
  9. 1 2 3 4 5 6 7 8 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. 1 2 3 4 5 6 "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, et al. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–1053. 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 (April 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): 9607–9616. doi:10.1074/jbc.274.14.9607. PMC 3715997. PMID 10092647.
  14. ↑ "PLA2G6". Genetics Home Reference. NCBI.Public Domain This article incorporates text from this source, which is in the public domain.
  15. ↑ Ozes B, Karagoz N, Schüle R, Rebelo A, Sobrido MJ, Harmuth F, et al. (November 2017). "PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia". Clinical Genetics. 92 (5): 534–539. doi:10.1111/cge.13008. PMC 5597457. PMID 28295203.
  16. 1 2 3 4 Gregory A, Kurian MA, Maher ER, Hogarth P, Hayflick SJ (1993). "PLA2G6-Associated Neurodegeneration". GeneReviews. University of Washington, Seattle. PMID 20301718. Retrieved 21 April 2022.
  17. ↑ "Hereditary spastic paraplegia". www.uniprot.org.
  18. ↑ Mick DU, Dennerlein S, Wiese H, Reinhold R, Pacheu-Grau D, Lorenzi I, et al. (December 2012). "MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation". Cell. 151 (7): 1528–1541. doi:10.1016/j.cell.2012.11.053. hdl:11858/00-001M-0000-000E-DDDF-4. PMID 23260140.

Further reading

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