PLA2G6: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''85 kDa calcium-independent [[phospholipase A2]]''' is an [[enzyme]] that in humans is encoded by the ''PLA2G6'' [[gene]].<ref name="pmid9417066">{{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 }}</ref><ref name="pmid16799181">{{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 }}</ref><ref name="pmid19029121">{{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 }}</ref><ref name="entrez">{{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 = }}</ref>
'''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]].<ref name="pmid9417066">{{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 }}</ref><ref name="pmid16799181">{{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 }}</ref><ref name="pmid19029121">{{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 }}</ref><ref name="entrez">{{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}}</ref><ref name = "uniprot">{{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 }}</ref><ref name = "uniprot0">{{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 }}</ref>
 
== Structure ==
The ''PLA2G6'' gene is located on the [[Locus (genetics)|p arm]] of [[chromosome 22]] at position 13.1 and it spans 80,605 base pairs.<ref name = entrez /> The ''PLA2G6'' gene produces an 18.6 kDa protein composed of 166 [[amino acids]].<ref name=COPaKB>{{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 }}</ref><ref name="url_COPaKB">{{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 }}</ref> The resulting protein's structure has been shown to contain a [[lipase]] [[protein motif|motif]] and 8 [[ankyrin repeats]].<ref name="pmid9417066"/> 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.<ref name="pmid9417066"/><ref name = "hi1">
{{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 }}</ref>


== Function ==
== 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]].<ref name="entrez"/> 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]].


The protein encoded by this gene is a [[phospholipase A2]] enzyme, a subclass of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, [[arachidonic acid]] release, leukotriene and prostaglandin synthesis, [[Fas receptor]]-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only two of them have been determined to date.<ref name="entrez"/>
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.<ref name = "GHR">{{ cite web| url = http://ghr.nlm.nih.gov/gene/PLA2G6 | work = Genetics Home Reference | title = PLA2G6 | publisher = NCBI}}{{PD-notice}}</ref> 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]].<ref name="entrez"/><ref name = "uniprot"/>
 
It addition, it has a role in [[cardiolipin]] (CL) [[acylation|deacylation]], and is required for both speed and directionality of [[monocyte]] [[CCL2|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.<ref name = "uniprot"/>  Several [[transcript variants]] encoding multiple [[isoforms]] have been described, but the full-length nature of only two of them have been determined to date.<ref name = "entrez"/>
 
==Catalytic activity==
Phosphatidylcholine + H2O = 1-acylglycerophosphocholine + a carboxylate.<ref name = "uniprot0"/><ref name = "uniprot"/>


==Model organisms==
==Model organisms==
[[Model organism]]s have been used in the study of PLA2G6 function. A conditional [[knockout mouse]] line called ''Pla2g6<sup>tm1a(EUCOMM)Wtsi</sup>'' was generated at the [[Wellcome Trust Sanger Institute]].<ref name="mgp_reference">{{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 }}</ref> Male and female animals underwent a standardized [[phenotypic screen]]<ref name="IMPCsearch_ref">{{cite web |url=http://www.mousephenotype.org/data/search?q=Pla2g6#fq=*:*&facet=gene |title=International Mouse Phenotyping Consortium}}</ref> to determine the effects of deletion.<ref name="pmid21677750">{{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 }}</ref><ref name="mouse_library">{{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 }}</ref><ref name="mouse_for_all_reasons">{{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 }}</ref><ref name="pmid23870131">{{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}}</ref> Additional screens performed:  - In-depth immunological phenotyping.<ref name="iii_ref">{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pla2g6&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}</ref>  
[[Model organism]]s have been used in the study of PLA2G6 function. A conditional [[knockout mouse]] line called ''Pla2g6<sup>tm1a(EUCOMM)Wtsi</sup>'' was generated at the [[Wellcome Trust Sanger Institute]].<ref name="mgp_reference">{{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 }}
</ref> Male and female animals underwent a standardized [[phenotypic screen]]<ref name="IMPCsearch_ref">{{cite web |url=http://www.mousephenotype.org/data/search?q=Pla2g6#fq=*:*&facet=gene |title=International Mouse Phenotyping Consortium}}</ref> to determine the effects of deletion.<ref name="pmid21677750">{{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 }}</ref><ref name="mouse_library">{{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 }}</ref><ref name="mouse_for_all_reasons">{{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 }}</ref><ref name="pmid23870131">{{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}}</ref> Additional screens performed:  - In-depth immunological phenotyping.<ref name="iii_ref">{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pla2g6&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}</ref>  
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|+ ''Pla2g6'' knockout mouse phenotype
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==Clinical==
==Clinical significance ==
Mutations in ''PLA2G6'' has been shown to result in mitochondrial deficiencies and associated disorders, including [[Neurodegeneration|Neurodegeneration with brain iron accumulation 2B (NBIA2B)]], [[Neurodegeneration|Neurodegeneration with brain iron accumulation 2A (NBIA2A)]], [[Parkinson's disease|Parkinson disease 14 (PARK14)]], and [[hereditary spastic paraplegia]].<ref name=Ozes2017>
 
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</ref><ref name = "uniprot"/><ref name = "uniprot0"/>
 
===Neurodegeneration with brain iron accumulation 2B (NBIA2B)===
[[Neurodegeneration|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 system|extrapyramidal]] dysfunction leading to rigidity, [[dystonia]], [[dysarthria]] and sensorimotor impairment.<ref name = "uniprot"/><ref name = "uniprot0"/>
 
===Neurodegeneration|Neurodegeneration with brain iron accumulation 2A (NBIA2A)===
[[Neurodegeneration|Neurodegeneration with brain iron accumulation 2A (NBIA2A)]] is a [[neurodegenerative disease]] characterized by pathologic [[axon|axonal swelling]] and [[spheroid|spheroid bodies]] in the [[central nervous system]]. Onset is within the first 2 years of life with death by age 10 years.<ref name = "uniprot"/><ref name = "uniprot0"/>
 
===Parkinson disease 14 (PARK14)===
[[Parkinson's disease|Parkinson disease 14 (PARK14)]] is an adult-onset progressive neurodegenerative disorder characterized by parkinsonism, [[dystonia]], severe cognitive decline, [[Brain|cerebral]] and [[cerebellar]] [[atrophy]] and absent iron in the [[basal ganglia]] on [[magnetic resonance imaging]].<ref name = "uniprot"/><ref name = "uniprot0"/>
 
===Hereditary spastic paraplegia===
[[Hereditary spastic paraplegia]]s 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.<ref>{{cite web |title=Hereditary spastic paraplegia |url=https://www.uniprot.org/keywords/KW-0890 |website=www.uniprot.org |language=en}}</ref>
 
==Interactions==
PLA2G6 has been shown to have [[Protein-protein interactions]] with the following.<ref name = "hi22">
 
{{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 }}</ref><ref name = "uniprot" />


Mutations in this gene have been associated with [[hereditary spastic paraplegia]].<ref name=Ozes2017>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</ref>
* [[BAG3]]
* [[ARF1]]
* [[CALM1]]
* [[HNRNPL]]


== References ==
== References ==
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{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Schröder HC, Perovic S, Kavsan V, Ushijima H, Müller WE | title = Mechanisms of prionSc- and HIV-1 gp120 induced neuronal cell death | journal = Neurotoxicology | volume = 19 | issue = 4-5 | pages = 683–8 | year = 1998 | pmid = 9745929 | doi =  }}
* {{cite journal | vauthors = Schröder HC, Perovic S, Kavsan V, Ushijima H, Müller WE | title = Mechanisms of prionSc- and HIV-1 gp120 induced neuronal cell death | journal = Neurotoxicology | volume = 19 | issue = 4-5 | pages = 683–8 | year = 1998 | pmid = 9745929 | doi =  }}
* {{cite journal | vauthors = Leslie CC | title = Regulation of arachidonic acid availability for eicosanoid production | journal = Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire | volume = 82 | issue = 1 | pages = 1–17 | date = Feb 2004 | pmid = 15052324 | doi = 10.1139/o03-080 }}
* {{cite journal | vauthors = Leslie CC | title = Regulation of arachidonic acid availability for eicosanoid production | journal = Biochemistry and Cell Biology | volume = 82 | issue = 1 | pages = 1–17 | date = Feb 2004 | pmid = 15052324 | doi = 10.1139/o03-080 }}
* {{cite journal | vauthors = Turk J, Ramanadham S | title = The expression and function of a group VIA calcium-independent phospholipase A2 (iPLA2beta) in beta-cells | journal = Canadian Journal of Physiology and Pharmacology | volume = 82 | issue = 10 | pages = 824–32 | date = Oct 2004 | pmid = 15573142 | doi = 10.1139/y04-064 }}
* {{cite journal | vauthors = Turk J, Ramanadham S | title = The expression and function of a group VIA calcium-independent phospholipase A2 (iPLA2beta) in beta-cells | journal = Canadian Journal of Physiology and Pharmacology | volume = 82 | issue = 10 | pages = 824–32 | date = Oct 2004 | pmid = 15573142 | doi = 10.1139/y04-064 }}
* {{cite journal | vauthors = Law MH, Cotton RG, Berger GE | title = The role of phospholipases A2 in schizophrenia | journal = Molecular Psychiatry | volume = 11 | issue = 6 | pages = 547–56 | date = Jun 2006 | pmid = 16585943 | doi = 10.1038/sj.mp.4001819 }}
* {{cite journal | vauthors = Law MH, Cotton RG, Berger GE | title = The role of phospholipases A2 in schizophrenia | journal = Molecular Psychiatry | volume = 11 | issue = 6 | pages = 547–56 | date = Jun 2006 | pmid = 16585943 | doi = 10.1038/sj.mp.4001819 }}
* {{cite journal | vauthors = Tang J, Kriz RW, Wolfman N, Shaffer M, Seehra J, Jones SS | title = A novel cytosolic calcium-independent phospholipase A2 contains eight ankyrin motifs | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8567–75 | date = Mar 1997 | pmid = 9079687 | doi = 10.1074/jbc.272.13.8567 }}
* {{cite journal | vauthors = Tang J, Kriz RW, Wolfman N, Shaffer M, Seehra J, Jones SS | title = A novel cytosolic calcium-independent phospholipase A2 contains eight ankyrin motifs | journal = The Journal of Biological Chemistry | volume = 272 | issue = 13 | pages = 8567–75 | date = Mar 1997 | pmid = 9079687 | doi = 10.1074/jbc.272.13.8567 }}
* {{cite journal | vauthors = Mavoungou E, Georges-Courbot MC, Poaty-Mavoungou V, Nguyen HT, Yaba P, Delicat A, Georges AJ, Russo-Marie F | title = HIV and SIV envelope glycoproteins induce phospholipase A2 activation in human and macaque lymphocytes | journal = Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology | volume = 16 | issue = 1 | pages = 1–9 | date = Sep 1997 | pmid = 9377118 | doi = 10.1097/00042560-199709010-00001 }}
* {{cite journal | vauthors = Mavoungou E, Georges-Courbot MC, Poaty-Mavoungou V, Nguyen HT, Yaba P, Delicat A, Georges AJ, Russo-Marie F | title = HIV and SIV envelope glycoproteins induce phospholipase A2 activation in human and macaque lymphocytes | journal = Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology | volume = 16 | issue = 1 | pages = 1–9 | date = Sep 1997 | pmid = 9377118 | doi = 10.1097/00042560-199709010-00001 }}
* {{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 }}
* {{cite journal | vauthors = Larsson Forsell PK, Kennedy BP, Claesson HE | title = The human calcium-independent phospholipase A2 gene multiple enzymes with distinct properties from a single gene | journal = European Journal of Biochemistry / FEBS | volume = 262 | issue = 2 | pages = 575–85 | date = Jun 1999 | pmid = 10336645 | doi = 10.1046/j.1432-1327.1999.00418.x }}
* {{cite journal | vauthors = Larsson Forsell PK, Kennedy BP, Claesson HE | title = The human calcium-independent phospholipase A2 gene multiple enzymes with distinct properties from a single gene | journal = European Journal of Biochemistry / FEBS | volume = 262 | issue = 2 | pages = 575–85 | date = Jun 1999 | pmid = 10336645 | doi = 10.1046/j.1432-1327.1999.00418.x }}
* {{cite journal | vauthors = Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP | title = The DNA sequence of human chromosome 22 | journal = Nature | volume = 402 | issue = 6761 | pages = 489–95 | date = Dec 1999 | pmid = 10591208 | doi = 10.1038/990031 }}
* {{cite journal | vauthors = Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP | title = The DNA sequence of human chromosome 22 | journal = Nature | volume = 402 | issue = 6761 | pages = 489–95 | date = Dec 1999 | pmid = 10591208 | doi = 10.1038/990031 }}
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* {{cite journal | vauthors = Cummings BS, McHowat J, Schnellmann RG | title = Role of an endoplasmic reticulum Ca2+-independent phospholipase A2 in cisplatin-induced renal cell apoptosis | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 308 | issue = 3 | pages = 921–8 | date = Mar 2004 | pmid = 14634037 | doi = 10.1124/jpet.103.060541 }}
* {{cite journal | vauthors = Cummings BS, McHowat J, Schnellmann RG | title = Role of an endoplasmic reticulum Ca2+-independent phospholipase A2 in cisplatin-induced renal cell apoptosis | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 308 | issue = 3 | pages = 921–8 | date = Mar 2004 | pmid = 14634037 | doi = 10.1124/jpet.103.060541 }}
* {{cite journal | vauthors = Bao S, Jin C, Zhang S, Turk J, Ma Z, Ramanadham S | title = Beta-cell calcium-independent group VIA phospholipase A(2) (iPLA(2)beta): tracking iPLA(2)beta movements in response to stimulation with insulin secretagogues in INS-1 cells | journal = Diabetes | volume = 53 Suppl 1 | issue = 90001 | pages = S186-9 | date = Feb 2004 | pmid = 14749286 | doi = 10.2337/diabetes.53.2007.S186 }}
* {{cite journal | vauthors = Bao S, Jin C, Zhang S, Turk J, Ma Z, Ramanadham S | title = Beta-cell calcium-independent group VIA phospholipase A(2) (iPLA(2)beta): tracking iPLA(2)beta movements in response to stimulation with insulin secretagogues in INS-1 cells | journal = Diabetes | volume = 53 Suppl 1 | issue = 90001 | pages = S186-9 | date = Feb 2004 | pmid = 14749286 | doi = 10.2337/diabetes.53.2007.S186 }}
* {{cite journal | vauthors = Tay HK, Melendez AJ | title = Fcgamma RI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells | journal = The Journal of Biological Chemistry | volume = 279 | issue = 21 | pages = 22505–13 | date = May 2004 | pmid = 15007079 | doi = 10.1074/jbc.M308788200 }}
* {{cite journal | vauthors = Tay HK, Melendez AJ | title = Fcgamma RI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells | journal = The Journal of Biological Chemistry | volume = 279 | issue = 21 | pages = 22505–13 | date = May 2004 | pmid = 15007079 | doi = 10.1074/jbc.M308788200 | pmc = 3617246 }}
* {{cite journal | vauthors = Tanaka H, Minakami R, Kanaya H, Sumimoto H | title = Catalytic residues of group VIB calcium-independent phospholipase A2 (iPLA2gamma) | journal = Biochemical and Biophysical Research Communications | volume = 320 | issue = 4 | pages = 1284–90 | date = Aug 2004 | pmid = 15249229 | doi = 10.1016/j.bbrc.2004.05.225 }}
* {{cite journal | vauthors = Tanaka H, Minakami R, Kanaya H, Sumimoto H | title = Catalytic residues of group VIB calcium-independent phospholipase A2 (iPLA2gamma) | journal = Biochemical and Biophysical Research Communications | volume = 320 | issue = 4 | pages = 1284–90 | date = Aug 2004 | pmid = 15249229 | doi = 10.1016/j.bbrc.2004.05.225 }}
{{refend}}
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Revision as of 14:57, 2 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Ensembl

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UniProt

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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.[1][2][3][4][5][6]

Structure

The 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]

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.[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 activity

Phosphatidylcholine + H2O = 1-acylglycerophosphocholine + a carboxylate.[6][5]

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.[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 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.[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 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.[19]

Interactions

PLA2G6 has been shown to have Protein-protein interactions with the following.[20][5]

References

  1. ↑ 1.0 1.1 1.2 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Entrez Gene: PLA2G6 phospholipase A2, group VI (cytosolic, calcium-independent)". This article incorporates text from this source, which is in the public domain.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 "PLA2G6 - 85/88 kDa calcium-independent phospholipase A2 - Homo sapiens (Human) - PLA2G6 gene & protein". Retrieved 2018-08-22.File:CC-BY-icon-80x15.png This article incorporates text available under the CC BY 4.0 license.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  7. ↑ 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.
  8. ↑ "85/88 kDa calcium-independent phospholipase A2". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  9. ↑ 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.
  10. ↑ "PLA2G6". Genetics Home Reference. NCBI. This article incorporates text from this source, which is in the public domain.
  11. ↑ 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.
  12. ↑ 12.0 12.1 "International Mouse Phenotyping Consortium".
  13. ↑ 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.
  14. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 17.0 17.1 "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. ↑ "Hereditary spastic paraplegia". www.uniprot.org.
  20. ↑ 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

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