| Structural highlights
Disease
PLD3_HUMAN Spinocerebellar ataxia type 46. The disease may be caused by variants affecting the gene represented in this entry. There is limited evidences for implication of PLD3 in SCA46. Knockout mice do not present signs of cerebellar degeneration or spinocerebellar ataxia at 9 months of age, challenging the interpretation of the suggested loss-of-function mechanism for PLD3 as the SCA46-causative gene.[1] Genetic variants in PLD3 have been suggested to be associated with an increased risk for Alzheimer disease (PubMed:24336208, PubMed:25832409). Further studies, however, did not support PLD3 involvement in this disease (PubMed:25832408, PubMed:25832410, PubMed:25832411, PubMed:25832413, PubMed:26411346). Futhermore, it is controversial whether PLD3 plays a role in amyloid precursor protein processing (APP) or not (PubMed:24336208). In a relevant Alzheimer's disease mouse model PLD3 deficiency does not affect APP metabolism or amyloid plaque burden (PubMed:28128235). However one study shown that PLD3 influences APP processing (PubMed:24336208).[2] [3] [4] [5] [6] [7] [8] [9]
Function
PLD3_HUMAN 5'->3' DNA exonuclease which digests single-stranded DNA (ssDNA) (PubMed:30312375). Regulates inflammatory cytokine responses via the degradation of nucleic acids, by reducing the concentration of ssDNA able to stimulate TLR9, a nucleotide-sensing receptor in collaboration with PLD4 (By similarity). May be important in myotube formation (PubMed:22428023). Plays a role in lysosomal homeostasis (PubMed:28128235). Involved in the regulation of endosomal protein sorting (PubMed:29368044).[UniProtKB:O35405][10] [11] [12] [13]
Publication Abstract from PubMed
Human 5'-3' exonuclease PLD3, a member of the phospholipase D family of enzymes, has been validated as a therapeutic target for treating Alzheimer's disease. Here, we have determined the crystal structure of the luminal domain of the enzyme at 2.3 A resolution, revealing a bilobal structure with a catalytic site located between the lobes. We then compared the structure with published crystal structures of other human PLD family members which revealed that a number of catalytic and lipid recognition residues, previously shown to be key for phospholipase activity, are not conserved or, are absent. This led us to test whether the enzyme is actually a phospholipase. We could not measure any phospholipase activity but the enzyme shows robust nuclease activity. Finally, we have mapped key single nucleotide polymorphisms onto the structure which reveals plausible reasons as to why they have an impact on Alzheimer's disease.
Crystal structure of Alzheimer's disease phospholipase D3 provides a molecular basis for understanding its normal and pathological functions.,Ishii K, Hermans SJ, Georgopoulou ME, Nero TL, Hancock NC, Crespi GAN, Gorman MA, Gooi JH, Parker MW FEBS J. 2024 Sep 26. doi: 10.1111/febs.17277. PMID:39325669[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gonzalez AC, Stroobants S, Reisdorf P, Gavin AL, Nemazee D, Schwudke D, D'Hooge R, Saftig P, Damme M. PLD3 and spinocerebellar ataxia. Brain. 2018 Nov 1;141(11):e78. PMID:30312375 doi:10.1093/brain/awy258
- ↑ Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, Harari O, Norton J, Budde J, Bertelsen S, Jeng AT, Cooper B, Skorupa T, Carrell D, Levitch D, Hsu S, Choi J, Ryten M, Sassi C, Bras J, Gibbs RJ, Hernandez DG, Lupton MK, Powell J, Forabosco P, Ridge PG, Corcoran CD, Tschanz JT, Norton MC, Munger RG, Schmutz C, Leary M, Demirci FY, Bamne MN, Wang X, Lopez OL, Ganguli M, Medway C, Turton J, Lord J, Braae A, Barber I, Brown K, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Morgan K, Rogaeva E, Singleton A, Hardy J, Kamboh MI, George-Hyslop PS, Cairns N, Morris JC, Kauwe JSK, Goate AM. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature. 2014 Jan 23;505(7484):550-554. PMID:24336208 doi:10.1038/nature12825
- ↑ Lambert JC, Grenier-Boley B, Bellenguez C, Pasquier F, Campion D, Dartigues JF, Berr C, Tzourio C, Amouyel P. PLD3 and sporadic Alzheimer's disease risk. Nature. 2015 Apr 2;520(7545):E1. PMID:25832408 doi:10.1038/nature14036
- ↑ Cruchaga C, Goate AM. Cruchaga & Goate reply. Nature. 2015 Apr 2;520(7545):E10. PMID:25832409 doi:10.1038/nature14041
- ↑ van der Lee SJ, Holstege H, Wong TH, Jakobsdottir J, Bis JC, Chouraki V, van Rooij JG, Grove ML, Smith AV, Amin N, Choi SH, Beiser AS, Garcia ME, van IJcken WF, Pijnenburg YA, Louwersheimer E, Brouwer RW, van den Hout MC, Oole E, Eirkisdottir G, Levy D, Rotter JI, Emilsson V, O'Donnell CJ, Aspelund T, Uitterlinden AG, Launer LJ, Hofman A, Boerwinkle E, Psaty BM, DeStefano AL, Scheltens P, Seshadri S, van Swieten JC, Gudnason V, van der Flier WM, Ikram MA, van Duijn CM. PLD3 variants in population studies. Nature. 2015 Apr 2;520(7545):E2-3. PMID:25832410 doi:10.1038/nature14038
- ↑ Heilmann S, Drichel D, Clarimon J, Fernández V, Lacour A, Wagner H, Thelen M, Hernández I, Fortea J, Alegret M, Blesa R, Mauleón A, Roca MR, Kornhuber J, Peters O, Heun R, Frölich L, Hüll M, Heneka MT, Rüther E, Riedel-Heller S, Scherer M, Wiltfang J, Jessen F, Becker T, Tárraga L, Boada M, Maier W, Lleó A, Ruiz A, Nöthen MM, Ramirez A. PLD3 in non-familial Alzheimer's disease. Nature. 2015 Apr 2;520(7545):E3-5. PMID:25832411 doi:10.1038/nature14039
- ↑ Hooli BV, Lill CM, Mullin K, Qiao D, Lange C, Bertram L, Tanzi RE. PLD3 gene variants and Alzheimer's disease. Nature. 2015 Apr 2;520(7545):E7-8. PMID:25832413 doi:10.1038/nature14040
- ↑ Cacace R, Van den Bossche T, Engelborghs S, Geerts N, Laureys A, Dillen L, Graff C, Thonberg H, Chiang HH, Pastor P, Ortega-Cubero S, Pastor MA, Diehl-Schmid J, Alexopoulos P, Benussi L, Ghidoni R, Binetti G, Nacmias B, Sorbi S, Sanchez-Valle R, Lladó A, Gelpi E, Almeida MR, Santana I, Tsolaki M, Koutroumani M, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Borroni B, Padovani A, Matej R, Rohan Z, Vandenbulcke M, Vandenberghe R, De Deyn PP, Cras P, van der Zee J, Sleegers K, Van Broeckhoven C. Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort. Hum Mutat. 2015 Dec;36(12):1226-35. PMID:26411346 doi:10.1002/humu.22908
- ↑ Fazzari P, Horre K, Arranz AM, Frigerio CS, Saito T, Saido TC, De Strooper B. PLD3 gene and processing of APP. Nature. 2017 Jan 25;541(7638):E1-E2. PMID:28128235 doi:10.1038/nature21030
- ↑ Osisami M, Ali W, Frohman MA. A role for phospholipase D3 in myotube formation. PLoS One. 2012;7(3):e33341. PMID:22428023 doi:10.1371/journal.pone.0033341
- ↑ Fazzari P, Horre K, Arranz AM, Frigerio CS, Saito T, Saido TC, De Strooper B. PLD3 gene and processing of APP. Nature. 2017 Jan 25;541(7638):E1-E2. PMID:28128235 doi:10.1038/nature21030
- ↑ Mukadam AS, Breusegem SY, Seaman MNJ. Analysis of novel endosome-to-Golgi retrieval genes reveals a role for PLD3 in regulating endosomal protein sorting and amyloid precursor protein processing. Cell Mol Life Sci. 2018 Jul;75(14):2613-2625. PMID:29368044 doi:10.1007/s00018-018-2752-9
- ↑ Gonzalez AC, Stroobants S, Reisdorf P, Gavin AL, Nemazee D, Schwudke D, D'Hooge R, Saftig P, Damme M. PLD3 and spinocerebellar ataxia. Brain. 2018 Nov 1;141(11):e78. PMID:30312375 doi:10.1093/brain/awy258
- ↑ Ishii K, Hermans SJ, Georgopoulou ME, Nero TL, Hancock NC, Crespi GAN, Gorman MA, Gooi JH, Parker MW. Crystal structure of Alzheimer's disease phospholipase D3 provides a molecular basis for understanding its normal and pathological functions. FEBS J. 2024 Sep 26. PMID:39325669 doi:10.1111/febs.17277
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