| 词条 | PLA2G6 | |||||||||||||||||||||||||||||||||||||||||||||
| 释义 |
StructureThe PLA2G6 gene is located on the p arm of chromosome 22 at position 13.1 and it spans 80,605 base pairs.[4] The PLA2G6 gene produces an 18.6 kDa protein composed of 166 amino acids.[7][8] The resulting protein's structure has been shown to contain a lipase motif and 8 ankyrin repeats.[1] 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.[1][9] FunctionThe PLA2G6 gene encodes for a phospholipase A2 enzyme, which is a subclass of enzyme that catalyzes the release of fatty acids from phospholipids.[4] 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.[10] 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.[4][5] 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.[5] Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only two of them have been determined to date.[4] Catalytic activityPhosphatidylcholine + H2O = 1-acylglycerophosphocholine + a carboxylate.[6][5] Model organismsModel 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.[11] Male and female animals underwent a standardized phenotypic screen[12] to determine the effects of deletion.[13][14][15][16] Additional screens performed: - In-depth immunological phenotyping.[17]
Clinical significanceMutations 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.[18][5][6] 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.[5][6]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.[5][6]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.[5][6]Hereditary spastic paraplegiaHereditary 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.[19]InteractionsPLA2G6 has been shown to have Protein-protein interactions with the following.[20][5]
References1. ^1 2 {{cite journal | vauthors = Larsson PK, Claesson HE, Kennedy BP | title = Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity | journal = The Journal of Biological Chemistry | volume = 273 | issue = 1 | pages = 207–14 | date = Jan 1998 | pmid = 9417066 | pmc = | doi = 10.1074/jbc.273.1.207 }} {{clear}}2. ^{{cite journal | vauthors = Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ | title = Characterization of the human patatin-like phospholipase family | journal = Journal of Lipid Research | volume = 47 | issue = 9 | pages = 1940–9 | date = Sep 2006 | pmid = 16799181 | pmc = | doi = 10.1194/jlr.M600185-JLR200 }} 3. ^{{cite journal | vauthors = Kienesberger PC, Oberer M, Lass A, Zechner R | title = Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions | journal = Journal of Lipid Research | volume = 50 Suppl | issue = | pages = S63–8 | date = Apr 2009 | pmid = 19029121 | pmc = 2674697 | doi = 10.1194/jlr.R800082-JLR200 }} 4. ^1 2 3 4 {{cite web | title = Entrez Gene: PLA2G6 phospholipase A2, group VI (cytosolic, calcium-independent)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8398| accessdate = }}{{PD-notice}} 5. ^1 2 3 4 5 6 7 8 {{Cite web|url=https://www.uniprot.org/uniprot/O60733|title= PLA2G6 - 85/88 kDa calcium-independent phospholipase A2 - Homo sapiens (Human) - PLA2G6 gene & protein|access-date=2018-08-22}}{{CC-notice|cc=by4 | url=https://www.uniprot.org/uniprot/O60733 | work = UniProt }} 6. ^1 2 3 4 5 {{cite journal | vauthors = | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }} 7. ^{{cite journal | vauthors = 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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = Oct 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }} 8. ^{{cite web | url = https://amino.heartproteome.org/web/protein/B0QYE9 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = 85/88 kDa calcium-independent phospholipase A2 }} 9. ^{{cite journal | vauthors = Ma Z, Wang X, Nowatzke W, Ramanadham S, Turk J | title = 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 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 14 | pages = 9607–16 | date = Apr 1999 | pmid = 10092647 | doi = 10.1074/jbc.274.14.9607 | pmc = 3715997 }} 10. ^{{ cite web| url = http://ghr.nlm.nih.gov/gene/PLA2G6 | work = Genetics Home Reference | title = PLA2G6 | publisher = NCBI}}{{PD-notice}} 11. ^{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice |author=Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }} 12. ^1 {{cite web |url=http://www.mousephenotype.org/data/search?q=Pla2g6#fq=**&facet=gene |title=International Mouse Phenotyping Consortium}} 13. ^{{cite journal | vauthors = 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 | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }} 14. ^{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = Jun 2011 | pmid = 21677718 | doi = 10.1038/474262a }} 15. ^{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }} 16. ^{{cite journal | vauthors = 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 | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | date = Jul 2013 | pmid = 23870131 | doi = 10.1016/j.cell.2013.06.022 | pmc=3717207}} 17. ^1 {{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pla2g6&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}} 18. ^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 19. ^{{cite web |title=Hereditary spastic paraplegia |url=https://www.uniprot.org/keywords/KW-0890 |website=www.uniprot.org |language=en}} 20. ^{{cite journal | vauthors = Mick DU, Dennerlein S, Wiese H, Reinhold R, Pacheu-Grau D, Lorenzi I, Sasarman F, Weraarpachai W, Shoubridge EA, Warscheid B, Rehling P | title = MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation | journal = Cell | volume = 151 | issue = 7 | pages = 1528–41 | date = December 2012 | pmid = 23260140 | doi = 10.1016/j.cell.2012.11.053 }} Further reading{{refbegin|33em}}
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