PLD3_HUMAN
ID PLD3_HUMAN Reviewed; 490 AA.
AC Q8IV08; Q92853; Q9BW87;
DT 20-MAR-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=5'-3' exonuclease PLD3 {ECO:0000305};
DE EC=3.1.16.1 {ECO:0000269|PubMed:30312375};
DE AltName: Full=Choline phosphatase 3;
DE AltName: Full=HindIII K4L homolog;
DE AltName: Full=Hu-K4 {ECO:0000303|PubMed:15794758};
DE AltName: Full=Phosphatidylcholine-hydrolyzing phospholipase D3;
DE AltName: Full=Phospholipase D3;
DE Short=PLD 3;
GN Name=PLD3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Mammary gland;
RX PubMed=9140189; DOI=10.1016/s0168-1702(96)01422-0;
RA Cao J.X., Koop B.F., Upton C.;
RT "A human homolog of the vaccinia virus HindIII K4L gene is a member of the
RT phospholipase D superfamily.";
RL Virus Res. 48:11-18(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Colon, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP SUBCELLULAR LOCATION, TOPOLOGY, TISSUE SPECIFICITY, AND GLYCOSYLATION.
RX PubMed=15794758; DOI=10.1111/j.1742-4658.2005.04601.x;
RA Munck A., Boehm C., Seibel N.M., Hashemol Hosseini Z., Hampe W.;
RT "Hu-K4 is a ubiquitously expressed type 2 transmembrane protein associated
RT with the endoplasmic reticulum.";
RL FEBS J. 272:1718-1726(2005).
RN [4]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-97 AND ASN-132.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-418, AND FUNCTION.
RX PubMed=22428023; DOI=10.1371/journal.pone.0033341;
RA Osisami M., Ali W., Frohman M.A.;
RT "A role for phospholipase D3 in myotube formation.";
RL PLoS ONE 7:E33341-E33341(2012).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [8]
RP FUNCTION, POSSIBLE INVOLVEMENT IN ALZHEIMER DISEASE, VARIANT MET-232,
RP TISSUE SPECIFICITY, AND INTERACTION WITH APP.
RX PubMed=24336208; DOI=10.1038/nature12825;
RG UK Brain Expression Consortium;
RA Cruchaga C., Karch C.M., Jin S.C., Benitez B.A., Cai Y., Guerreiro R.,
RA Harari O., Norton J., Budde J., Bertelsen S., Jeng A.T., Cooper B.,
RA Skorupa T., Carrell D., Levitch D., Hsu S., Choi J., Ryten M., Hardy J.,
RA Ryten M., Trabzuni D., Weale M.E., Ramasamy A., Smith C., Sassi C.,
RA Bras J., Gibbs J.R., Hernandez D.G., Lupton M.K., Powell J., Forabosco P.,
RA Ridge P.G., Corcoran C.D., Tschanz J.T., Norton M.C., Munger R.G.,
RA Schmutz C., Leary M., Demirci F.Y., Bamne M.N., Wang X., Lopez O.L.,
RA Ganguli M., Medway C., Turton J., Lord J., Braae A., Barber I., Brown K.,
RA Passmore P., Craig D., Johnston J., McGuinness B., Todd S., Heun R.,
RA Kolsch H., Kehoe P.G., Hooper N.M., Vardy E.R., Mann D.M.,
RA Pickering-Brown S., Brown K., Kalsheker N., Lowe J., Morgan K.,
RA David Smith A., Wilcock G., Warden D., Holmes C., Pastor P.,
RA Lorenzo-Betancor O., Brkanac Z., Scott E., Topol E., Morgan K., Rogaeva E.,
RA Singleton A.B., Hardy J., Kamboh M.I., St George-Hyslop P., Cairns N.,
RA Morris J.C., Kauwe J.S., Goate A.M.;
RT "Rare coding variants in the phospholipase D3 gene confer risk for
RT Alzheimer's disease.";
RL Nature 505:550-554(2014).
RN [9]
RP LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANTS SER-63; ALA-76;
RP MET-159; CYS-162; SER-173; GLY-175; CYS-188; HIS-222; MET-232; GLN-242;
RP GLY-249; CYS-272; SER-284; VAL-293; LEU-297; TYR-300; PRO-308; ILE-358;
RP ALA-426 AND ARG-429.
RX PubMed=26411346; DOI=10.1002/humu.22908;
RG Belgium Neurology (BELNEU) Consortium and the European Early-Onset Dementia (EU EOD) Consortium;
RA Cacace R., Van den Bossche T., Engelborghs S., Geerts N., Laureys A.,
RA Dillen L., Graff C., Thonberg H., Chiang H.H., Pastor P., Ortega-Cubero S.,
RA Pastor M.A., Diehl-Schmid J., Alexopoulos P., Benussi L., Ghidoni R.,
RA Binetti G., Nacmias B., Sorbi S., Sanchez-Valle R., Llado A., Gelpi E.,
RA Almeida M.R., Santana I., Tsolaki M., Koutroumani M., Clarimon J., Lleo A.,
RA Fortea J., de Mendonca A., Martins M., Borroni B., Padovani A., Matej R.,
RA Rohan Z., Vandenbulcke M., Vandenberghe R., De Deyn P.P., Cras P.,
RA van der Zee J., Sleegers K., Van Broeckhoven C.;
RT "Rare variants in PLD3 do not affect risk for early-onset Alzheimer disease
RT in a European consortium cohort.";
RL Hum. Mutat. 36:1226-1235(2015).
RN [10]
RP LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX PubMed=25832408; DOI=10.1038/nature14036;
RA Lambert J.C., Grenier-Boley B., Bellenguez C., Pasquier F., Campion D.,
RA Dartigues J.F., Berr C., Tzourio C., Amouyel P.;
RT "PLD3 and sporadic Alzheimer's disease risk.";
RL Nature 520:E1-E1(2015).
RN [11]
RP LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX PubMed=25832410; DOI=10.1038/nature14038;
RA van der Lee S.J., Holstege H., Wong T.H., Jakobsdottir J., Bis J.C.,
RA Chouraki V., van Rooij J.G., Grove M.L., Smith A.V., Amin N., Choi S.H.,
RA Beiser A.S., Garcia M.E., van Ijcken W.F., Pijnenburg Y.A.,
RA Louwersheimer E., Brouwer R.W., van den Hout M.C., Oole E.,
RA Eirkisdottir G., Levy D., Rotter J.I., Emilsson V., O'Donnell C.J.,
RA Aspelund T., Uitterlinden A.G., Launer L.J., Hofman A., Boerwinkle E.,
RA Psaty B.M., DeStefano A.L., Scheltens P., Seshadri S., van Swieten J.C.,
RA Gudnason V., van der Flier W.M., Ikram M.A., van Duijn C.M.;
RT "PLD3 variants in population studies.";
RL Nature 520:E2-E3(2015).
RN [12]
RP LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX PubMed=25832411; DOI=10.1038/nature14039;
RA Heilmann S., Drichel D., Clarimon J., Fernandez V., Lacour A., Wagner H.,
RA Thelen M., Hernandez I., Fortea J., Alegret M., Blesa R., Mauleon A.,
RA Roca M.R., Kornhuber J., Peters O., Heun R., Froelich L., Huell M.,
RA Heneka M.T., Ruether E., Riedel-Heller S., Scherer M., Wiltfang J.,
RA Jessen F., Becker T., Tarraga L., Boada M., Maier W., Lleo A., Ruiz A.,
RA Noethen M.M., Ramirez A.;
RT "PLD3 in non-familial Alzheimer's disease.";
RL Nature 520:E3-E5(2015).
RN [13]
RP LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX PubMed=25832413; DOI=10.1038/nature14040;
RA Hooli B.V., Lill C.M., Mullin K., Qiao D., Lange C., Bertram L.,
RA Tanzi R.E.;
RT "PLD3 gene variants and Alzheimer's disease.";
RL Nature 520:E7-E8(2015).
RN [14]
RP POSSIBLE INVOLVEMENT IN ALZHEIMER DISEASE, AND VARIANT MET-232.
RX PubMed=25832409; DOI=10.1038/nature14041;
RA Cruchaga C., Goate A.M.;
RT "Cruchaga & Goate reply.";
RL Nature 520:E10-E10(2015).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [16]
RP INVOLVEMENT IN SCA46, VARIANT SCA46 PRO-308, GLYCOSYLATION,
RP CHARACTERIZATION OF VARIANT SCA46 PRO-308, AND POSSIBLE.
RX PubMed=29053796; DOI=10.1093/brain/awx251;
RA Nibbeling E.A.R., Duarri A., Verschuuren-Bemelmans C.C., Fokkens M.R.,
RA Karjalainen J.M., Smeets C.J.L.M., de Boer-Bergsma J.J., van der Vries G.,
RA Dooijes D., Bampi G.B., van Diemen C., Brunt E., Ippel E., Kremer B.,
RA Vlak M., Adir N., Wijmenga C., van de Warrenburg B.P.C., Franke L.,
RA Sinke R.J., Verbeek D.S.;
RT "Exome sequencing and network analysis identifies shared mechanisms
RT underlying spinocerebellar ataxia.";
RL Brain 140:2860-2878(2017).
RN [17]
RP LACK OF INVOLVEMENT IN ALZHEIMER DISEASE, TISSUE SPECIFICITY,
RP CHARACTERIZATION OF VARIANTS MET-232, FUNCTION, AND MUTAGENESIS OF LYS-418.
RX PubMed=28128235; DOI=10.1038/nature21030;
RA Fazzari P., Horre K., Arranz A.M., Frigerio C.S., Saito T., Saido T.C.,
RA De Strooper B.;
RT "PLD3 gene and processing of APP.";
RL Nature 541:E1-E2(2017).
RN [18]
RP CHARACTERIZATION OF VARIANT SCA46 PRO-308, FUNCTION, SUBCELLULAR LOCATION,
RP AND CATALYTIC ACTIVITY.
RX PubMed=30312375; DOI=10.1093/brain/awy258;
RA Gonzalez A.C., Stroobants S., Reisdorf P., Gavin A.L., Nemazee D.,
RA Schwudke D., D'Hooge R., Saftig P., Damme M.;
RT "PLD3 and spinocerebellar ataxia.";
RL Brain 141:E78-E78(2018).
RN [19]
RP FUNCTION, SUBCELLULAR LOCATION, AND TOPOLOGY.
RX PubMed=29368044; DOI=10.1007/s00018-018-2752-9;
RA Mukadam A.S., Breusegem S.Y., Seaman M.N.J.;
RT "Analysis of novel endosome-to-Golgi retrieval genes reveals a role for
RT PLD3 in regulating endosomal protein sorting and amyloid precursor protein
RT processing.";
RL Cell. Mol. Life Sci. 75:2613-2625(2018).
RN [20]
RP SUBCELLULAR LOCATION, GLYCOSYLATION, AND MUTAGENESIS OF TYR-7.
RX PubMed=29386126; DOI=10.1016/j.celrep.2017.12.100;
RA Gonzalez A.C., Schweizer M., Jagdmann S., Bernreuther C., Reinheckel T.,
RA Saftig P., Damme M.;
RT "Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes.";
RL Cell Rep. 22:1040-1053(2018).
CC -!- FUNCTION: 5'->3' DNA exonuclease which digests single-stranded DNA
CC (ssDNA) (PubMed:30312375). Regulates inflammatory cytokine responses
CC via the degradation of nucleic acids, by reducing the concentration of
CC ssDNA able to stimulate TLR9, a nucleotide-sensing receptor in
CC collaboration with PLD4 (By similarity). May be important in myotube
CC formation (PubMed:22428023). Plays a role in lysosomal homeostasis
CC (PubMed:28128235). Involved in the regulation of endosomal protein
CC sorting (PubMed:29368044). {ECO:0000250|UniProtKB:O35405,
CC ECO:0000269|PubMed:22428023, ECO:0000269|PubMed:28128235,
CC ECO:0000269|PubMed:29368044, ECO:0000269|PubMed:30312375}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Exonucleolytic cleavage in the 5'- to 3'-direction to yield
CC nucleoside 3'-phosphates.; EC=3.1.16.1;
CC Evidence={ECO:0000269|PubMed:30312375};
CC -!- SUBUNIT: Interacts with APP. {ECO:0000269|PubMed:24336208}.
CC -!- INTERACTION:
CC Q8IV08; Q8TBE1: CNIH3; NbExp=3; IntAct=EBI-2689908, EBI-12208021;
CC Q8IV08; P19838: NFKB1; NbExp=2; IntAct=EBI-2689908, EBI-300010;
CC Q8IV08; P35372-10: OPRM1; NbExp=3; IntAct=EBI-2689908, EBI-12807478;
CC Q8IV08; Q9NRQ5: SMCO4; NbExp=3; IntAct=EBI-2689908, EBI-8640191;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:22428023}; Single-pass
CC type II membrane protein {ECO:0000269|PubMed:15794758,
CC ECO:0000269|PubMed:22428023}. Lysosome lumen
CC {ECO:0000269|PubMed:29386126, ECO:0000269|PubMed:30312375}. Early
CC endosome membrane {ECO:0000269|PubMed:29386126}; Single-pass type II
CC membrane protein {ECO:0000269|PubMed:15794758,
CC ECO:0000269|PubMed:22428023}. Late endosome membrane
CC {ECO:0000269|PubMed:29386126}; Single-pass type II membrane protein
CC {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:22428023}. Golgi
CC apparatus membrane {ECO:0000269|PubMed:29368044}; Single-pass type II
CC membrane protein {ECO:0000269|PubMed:29368044}. Endosome membrane
CC {ECO:0000269|PubMed:29368044}; Single-pass type II membrane protein
CC {ECO:0000269|PubMed:29368044}. Note=Localizes to ER-associated vesicles
CC in differentiating myotubes (PubMed:22428023). The soluble form in
CC lysosome arises by proteolytic processing of the membrane-bound form
CC (PubMed:29386126). Colocalizes with APP in endosomes (PubMed:29368044).
CC {ECO:0000269|PubMed:22428023, ECO:0000269|PubMed:29368044,
CC ECO:0000269|PubMed:29386126}.
CC -!- TISSUE SPECIFICITY: Widely expressed. In the brain, high levels of
CC expression are detected in the frontal, temporal and occipital cortices
CC and hippocampus. Expressed at low level in corpus callosum.
CC {ECO:0000269|PubMed:15794758, ECO:0000269|PubMed:24336208}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:15794758,
CC ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:29053796,
CC ECO:0000269|PubMed:29386126}.
CC -!- PTM: Proteolytically processed to a soluble form that is stable within
CC endosomes and lysosomes. During transport through the secretory pathway
CC becomes proteolysed by cysteine proteases, thereby releasing a stable
CC soluble lysosomal lumenal polypeptide, whereas the transmembrane-bound
CC fragment is rapidly degraded. Its transport route to lysosomes involves
CC ubiquitination and the ESCRT complex. {ECO:0000269|PubMed:29386126}.
CC -!- PTM: Ubiquitinated at N-terminus. Ubiquitination mediates sorting into
CC lysosomes. {ECO:0000269|PubMed:29386126}.
CC -!- DISEASE: Spinocerebellar ataxia 46 (SCA46) [MIM:617770]: A form of
CC spinocerebellar ataxia, a clinically and genetically heterogeneous
CC group of cerebellar disorders. Patients show progressive incoordination
CC of gait and often poor coordination of hands, speech and eye movements,
CC due to degeneration of the cerebellum with variable involvement of the
CC brainstem and spinal cord. SCA46 is a slowly progressive, autosomal
CC dominant form with onset in adulthood. {ECO:0000269|PubMed:29053796,
CC ECO:0000269|PubMed:30312375}. Note=The disease may be caused by
CC variants affecting the gene represented in this entry. There is limited
CC evidences for implication of PLD3 in SCA46. Knockout mice do not
CC present signs of cerebellar degeneration or spinocerebellar ataxia at 9
CC months of age, challenging the interpretation of the suggested loss-of-
CC function mechanism for PLD3 as the SCA46-causative gene.
CC {ECO:0000269|PubMed:30312375}.
CC -!- DISEASE: Note=Genetic variants in PLD3 have been suggested to be
CC associated with an increased risk for Alzheimer disease
CC (PubMed:24336208, PubMed:25832409). Further studies, however, did not
CC support PLD3 involvement in this disease (PubMed:25832408,
CC PubMed:25832411, PubMed:25832413, PubMed:25832410, PubMed:26411346).
CC Futhermore, it is controversial whether PLD3 plays a role in amyloid
CC precursor protein processing (APP) or not (PubMed:24336208). In a
CC relevant Alzheimer's disease mouse model PLD3 deficiency does not
CC affect APP metabolism or amyloid plaque burden (PubMed:28128235).
CC However one study shown that PLD3 influences APP processing
CC (PubMed:24336208). {ECO:0000269|PubMed:24336208,
CC ECO:0000269|PubMed:25832408, ECO:0000269|PubMed:25832409,
CC ECO:0000269|PubMed:25832410, ECO:0000269|PubMed:25832411,
CC ECO:0000269|PubMed:25832413, ECO:0000269|PubMed:26411346,
CC ECO:0000269|PubMed:28128235}.
CC -!- SIMILARITY: Belongs to the phospholipase D family. {ECO:0000305}.
CC -!- CAUTION: It was initially thought that PDL3 has phospholipase D
CC activity due to its HKD motifs. The second HKD motif contains Glu
CC instead of the canonical Asp. Its enzyme activity is therefore unsure.
CC Catalytic phospholipase D activity is still controversial
CC (PubMed:29053796, PubMed:30312375). Its closest homolog PLD4, exhibits
CC no phospholipase activity (By similarity).
CC {ECO:0000250|UniProtKB:Q8BG07, ECO:0000269|PubMed:29053796,
CC ECO:0000269|PubMed:30312375}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB16799.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; U60644; AAB16799.1; ALT_FRAME; mRNA.
DR EMBL; BC000553; AAH00553.2; -; mRNA.
DR EMBL; BC036327; AAH36327.1; -; mRNA.
DR EMBL; BC096820; AAH96820.1; -; mRNA.
DR CCDS; CCDS33027.1; -.
DR RefSeq; NP_001026866.1; NM_001031696.3.
DR RefSeq; NP_001278240.1; NM_001291311.1.
DR RefSeq; NP_036400.2; NM_012268.3.
DR RefSeq; XP_005258761.1; XM_005258704.1.
DR RefSeq; XP_005258764.1; XM_005258707.4.
DR RefSeq; XP_005258765.1; XM_005258708.3.
DR RefSeq; XP_005258766.1; XM_005258709.4.
DR RefSeq; XP_005258767.1; XM_005258710.4.
DR RefSeq; XP_006723185.1; XM_006723122.1.
DR RefSeq; XP_011524994.1; XM_011526692.1.
DR RefSeq; XP_011524995.1; XM_011526693.1.
DR RefSeq; XP_016882035.1; XM_017026546.1.
DR RefSeq; XP_016882036.1; XM_017026547.1.
DR RefSeq; XP_016882037.1; XM_017026548.1.
DR RefSeq; XP_016882038.1; XM_017026549.1.
DR AlphaFoldDB; Q8IV08; -.
DR SMR; Q8IV08; -.
DR BioGRID; 117173; 110.
DR IntAct; Q8IV08; 39.
DR MINT; Q8IV08; -.
DR STRING; 9606.ENSP00000387050; -.
DR GlyConnect; 1604; 14 N-Linked glycans (3 sites).
DR GlyGen; Q8IV08; 6 sites, 14 N-linked glycans (3 sites), 1 O-linked glycan (1 site).
DR iPTMnet; Q8IV08; -.
DR PhosphoSitePlus; Q8IV08; -.
DR BioMuta; PLD3; -.
DR DMDM; 74750647; -.
DR EPD; Q8IV08; -.
DR jPOST; Q8IV08; -.
DR MassIVE; Q8IV08; -.
DR MaxQB; Q8IV08; -.
DR PaxDb; Q8IV08; -.
DR PeptideAtlas; Q8IV08; -.
DR PRIDE; Q8IV08; -.
DR ProteomicsDB; 70639; -.
DR TopDownProteomics; Q8IV08; -.
DR Antibodypedia; 2295; 140 antibodies from 23 providers.
DR DNASU; 23646; -.
DR Ensembl; ENST00000356508.9; ENSP00000348901.5; ENSG00000105223.20.
DR Ensembl; ENST00000409281.5; ENSP00000387022.1; ENSG00000105223.20.
DR Ensembl; ENST00000409419.5; ENSP00000386293.1; ENSG00000105223.20.
DR Ensembl; ENST00000409587.5; ENSP00000387050.1; ENSG00000105223.20.
DR Ensembl; ENST00000409735.9; ENSP00000386938.3; ENSG00000105223.20.
DR GeneID; 23646; -.
DR KEGG; hsa:23646; -.
DR MANE-Select; ENST00000409735.9; ENSP00000386938.3; NM_012268.4; NP_036400.2.
DR UCSC; uc002onj.5; human.
DR CTD; 23646; -.
DR DisGeNET; 23646; -.
DR GeneCards; PLD3; -.
DR HGNC; HGNC:17158; PLD3.
DR HPA; ENSG00000105223; Tissue enhanced (pituitary).
DR MalaCards; PLD3; -.
DR MIM; 615698; gene.
DR MIM; 617770; phenotype.
DR neXtProt; NX_Q8IV08; -.
DR NIAGADS; ENSG00000105223; -.
DR OpenTargets; ENSG00000105223; -.
DR Orphanet; 589522; Spinocerebellar ataxia type 46.
DR PharmGKB; PA134887482; -.
DR VEuPathDB; HostDB:ENSG00000105223; -.
DR eggNOG; KOG3603; Eukaryota.
DR GeneTree; ENSGT00950000183059; -.
DR HOGENOM; CLU_027021_0_0_1; -.
DR InParanoid; Q8IV08; -.
DR OMA; THFIPNT; -.
DR OrthoDB; 1057467at2759; -.
DR PhylomeDB; Q8IV08; -.
DR TreeFam; TF313378; -.
DR PathwayCommons; Q8IV08; -.
DR Reactome; R-HSA-1483148; Synthesis of PG.
DR Reactome; R-HSA-2029485; Role of phospholipids in phagocytosis.
DR SignaLink; Q8IV08; -.
DR SIGNOR; Q8IV08; -.
DR BioGRID-ORCS; 23646; 15 hits in 1089 CRISPR screens.
DR ChiTaRS; PLD3; human.
DR GenomeRNAi; 23646; -.
DR Pharos; Q8IV08; Tbio.
DR PRO; PR:Q8IV08; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q8IV08; protein.
DR Bgee; ENSG00000105223; Expressed in adenohypophysis and 195 other tissues.
DR ExpressionAtlas; Q8IV08; baseline and differential.
DR Genevisible; Q8IV08; HS.
DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB.
DR GO; GO:0043202; C:lysosomal lumen; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IEA:Ensembl.
DR GO; GO:0004630; F:phospholipase D activity; TAS:ProtInc.
DR GO; GO:0045145; F:single-stranded DNA 5'-3' exodeoxyribonuclease activity; IDA:UniProtKB.
DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0014902; P:myotube differentiation; IDA:UniProtKB.
DR GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
DR InterPro; IPR032803; PLDc_3.
DR InterPro; IPR001736; PLipase_D/transphosphatidylase.
DR Pfam; PF00614; PLDc; 1.
DR Pfam; PF13918; PLDc_3; 1.
DR SMART; SM00155; PLDc; 2.
DR PROSITE; PS50035; PLD; 2.
PE 1: Evidence at protein level;
KW Disease variant; Endoplasmic reticulum; Endosome; Exonuclease;
KW Glycoprotein; Golgi apparatus; Hydrolase; Immunity; Inflammatory response;
KW Lysosome; Membrane; Neurodegeneration; Nuclease; Reference proteome;
KW Repeat; Signal-anchor; Spinocerebellar ataxia; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..490
FT /note="5'-3' exonuclease PLD3"
FT /id="PRO_0000280326"
FT TOPO_DOM 1..38
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:22428023"
FT TRANSMEM 39..59
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000269|PubMed:22428023"
FT TOPO_DOM 60..490
FT /note="Lumenal"
FT /evidence="ECO:0000305|PubMed:22428023"
FT DOMAIN 196..223
FT /note="PLD phosphodiesterase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT DOMAIN 411..437
FT /note="PLD phosphodiesterase 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 201
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 203
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT ACT_SITE 208
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00153"
FT CARBOHYD 97
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT CARBOHYD 132
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT VARIANT 63
FT /note="G -> S (in dbSNP:rs142070038)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075905"
FT VARIANT 76
FT /note="P -> A (in dbSNP:rs138674695)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075906"
FT VARIANT 159
FT /note="V -> M (in dbSNP:rs374184677)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075907"
FT VARIANT 162
FT /note="R -> C"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075908"
FT VARIANT 173
FT /note="P -> S (in dbSNP:rs866850284)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075909"
FT VARIANT 175
FT /note="A -> G (in dbSNP:rs780604999)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075910"
FT VARIANT 188
FT /note="R -> C (in dbSNP:rs1326374111)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075911"
FT VARIANT 222
FT /note="R -> H (in dbSNP:rs765630414)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075912"
FT VARIANT 232
FT /note="V -> M (originally reported as risk factor for
FT Alzheimer disease; unknown pathological significance; does
FT not reduce either amyloid-beta levels or APP expression;
FT dbSNP:rs145999145)"
FT /evidence="ECO:0000269|PubMed:24336208,
FT ECO:0000269|PubMed:25832408, ECO:0000269|PubMed:25832409,
FT ECO:0000269|PubMed:25832410, ECO:0000269|PubMed:25832411,
FT ECO:0000269|PubMed:25832413, ECO:0000269|PubMed:26411346,
FT ECO:0000269|PubMed:28128235"
FT /id="VAR_071186"
FT VARIANT 242
FT /note="R -> Q (in dbSNP:rs757965784)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075913"
FT VARIANT 249
FT /note="E -> G (in dbSNP:rs746715924)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075914"
FT VARIANT 272
FT /note="R -> C (in dbSNP:rs144312764)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075915"
FT VARIANT 284
FT /note="N -> S (in dbSNP:rs200274020)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075916"
FT VARIANT 293
FT /note="A -> V (in dbSNP:rs368737000)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075917"
FT VARIANT 297
FT /note="P -> L"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075918"
FT VARIANT 300
FT /note="C -> Y (in dbSNP:rs146083475)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075919"
FT VARIANT 308
FT /note="L -> P (in SCA46; unknown pathological significance;
FT reduced lysosomal localization; induces retention in the
FT ER; reduction of proteolityc cleavage; loss of exonuclease
FT activity; dbSNP:rs537053537)"
FT /evidence="ECO:0000269|PubMed:26411346,
FT ECO:0000269|PubMed:29053796, ECO:0000269|PubMed:30312375"
FT /id="VAR_075920"
FT VARIANT 358
FT /note="V -> I (in dbSNP:rs370488565)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075921"
FT VARIANT 426
FT /note="T -> A (in dbSNP:rs745463234)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075922"
FT VARIANT 429
FT /note="G -> R (in dbSNP:rs986006936)"
FT /evidence="ECO:0000269|PubMed:26411346"
FT /id="VAR_075923"
FT MUTAGEN 7
FT /note="Y->A: Slightly increased plasma membrane
FT localization, does not affect delivery to lysosomes."
FT /evidence="ECO:0000269|PubMed:29386126"
FT MUTAGEN 418
FT /note="K->R: Impairs myotube formation."
FT /evidence="ECO:0000269|PubMed:22428023,
FT ECO:0000269|PubMed:28128235"
FT CONFLICT 473
FT /note="S -> I (in Ref. 1; AAB16799)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 490 AA; 54705 MW; 444EC4D02F5610F1 CRC64;
MKPKLMYQEL KVPAEEPANE LPMNEIEAWK AAEKKARWVL LVLILAVVGF GALMTQLFLW
EYGDLHLFGP NQRPAPCYDP CEAVLVESIP EGLDFPNAST GNPSTSQAWL GLLAGAHSSL
DIASFYWTLT NNDTHTQEPS AQQGEEVLRQ LQTLAPKGVN VRIAVSKPSG PQPQADLQAL
LQSGAQVRMV DMQKLTHGVL HTKFWVVDQT HFYLGSANMD WRSLTQVKEL GVVMYNCSCL
ARDLTKIFEA YWFLGQAGSS IPSTWPRFYD TRYNQETPME ICLNGTPALA YLASAPPPLC
PSGRTPDLKA LLNVVDNARS FIYVAVMNYL PTLEFSHPHR FWPAIDDGLR RATYERGVKV
RLLISCWGHS EPSMRAFLLS LAALRDNHTH SDIQVKLFVV PADEAQARIP YARVNHNKYM
VTERATYIGT SNWSGNYFTE TAGTSLLVTQ NGRGGLRSQL EAIFLRDWDS PYSHDLDTSA
DSVGNACRLL
