ID DGLA_HUMAN Reviewed; 1042 AA. AC Q9Y4D2; A0A024R517; A7E233; Q6WQJ0; DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot. DT 05-SEP-2006, sequence version 3. DT 24-JAN-2024, entry version 163. DE RecName: Full=Diacylglycerol lipase-alpha; DE Short=DAGL-alpha; DE Short=DGL-alpha; DE EC=3.1.1.116 {ECO:0000269|PubMed:14610053, ECO:0000269|PubMed:23502535, ECO:0000269|PubMed:26668358}; DE AltName: Full=Neural stem cell-derived dendrite regulator {ECO:0000303|Ref.1}; DE AltName: Full=Sn1-specific diacylglycerol lipase alpha {ECO:0000303|PubMed:14610053}; GN Name=DAGLA; Synonyms=C11orf11, KIAA0659, NSDDR {ECO:0000303|Ref.1}; 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]. RA Horiguchi S., Tashiro K., Takahashi J., Hashimoto N., Nakano I., RA Tsuchida Y., Hirai H., Honjo T.; RT "NSDDR a novel tetra-spanning transmembrane protein with a unique RT integration pattern to the plasma membrane regulates the extension of the RT dendritic trees of Purkinje cells."; RL Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=9734811; DOI=10.1093/dnares/5.3.169; RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., RA Nomura N., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. X. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 5:169-176(1998). RN [3] RP SEQUENCE REVISION. RX PubMed=12168954; DOI=10.1093/dnares/9.3.99; RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.; RT "Construction of expression-ready cDNA clones for KIAA genes: manual RT curation of 330 KIAA cDNA clones."; RL DNA Res. 9:99-106(2002). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [7] RP FUNCTION, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, RP TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY. RX PubMed=14610053; DOI=10.1083/jcb.200305129; RA Bisogno T., Howell F., Williams G., Minassi A., Cascio M.G., Ligresti A., RA Matias I., Schiano-Moriello A., Paul P., Williams E.-J., Gangadharan U., RA Hobbs C., Di Marzo V., Doherty P.; RT "Cloning of the first sn1-DAG lipases points to the spatial and temporal RT regulation of endocannabinoid signaling in the brain."; RL J. Cell Biol. 163:463-468(2003). RN [8] RP TISSUE SPECIFICITY. RX PubMed=16051747; DOI=10.1124/mol.105.013961; RA Jung K.-M., Mangieri R., Stapleton C., Kim J., Fegley D., Wallace M., RA Mackie K., Piomelli D.; RT "Stimulation of endocannabinoid formation in brain slice cultures through RT activation of group I metabotropic glutamate receptors."; RL Mol. Pharmacol. 68:1196-1202(2005). RN [9] RP CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, RP PHOSPHORYLATION AT SER-782 AND SER-808, INTERACTION WITH CAMK2A, RP MUTAGENESIS OF SER-782 AND SER-808, AND ACTIVITY REGULATION. RX PubMed=23502535; DOI=10.1038/nn.3353; RA Shonesy B.C., Wang X., Rose K.L., Ramikie T.S., Cavener V.S., Rentz T., RA Baucum A.J. II, Jalan-Sakrikar N., Mackie K., Winder D.G., Patel S., RA Colbran R.J.; RT "CaMKII regulates diacylglycerol lipase-alpha and striatal endocannabinoid RT signaling."; RL Nat. Neurosci. 16:456-463(2013). RN [10] RP SUBCELLULAR LOCATION. RX PubMed=27595600; DOI=10.1016/j.mcn.2016.08.011; RA Zhou Y., Howell F.V., Glebov O.O., Albrecht D., Williams G., Doherty P.; RT "Regulated endosomal trafficking of Diacylglycerol lipase alpha (DAGLalpha) RT generates distinct cellular pools; implications for endocannabinoid RT signaling."; RL Mol. Cell. Neurosci. 76:76-86(2016). RN [11] RP CATALYTIC ACTIVITY, FUNCTION, AND ACTIVITY REGULATION. RX PubMed=26668358; DOI=10.1073/pnas.1522364112; RA Ogasawara D., Deng H., Viader A., Baggelaar M.P., Breman A., den Dulk H., RA van den Nieuwendijk A.M., van den Nieuwendijk A.M., Soethoudt M., RA van der Wel T., Zhou J., Overkleeft H.S., Sanchez-Alavez M., Mori S., RA Mo S., Nguyen W., Conti B., Liu X., Chen Y., Liu Q.S., Cravatt B.F., RA van der Stelt M.; RT "Rapid and profound rewiring of brain lipid signaling networks by acute RT diacylglycerol lipase inhibition."; RL Proc. Natl. Acad. Sci. U.S.A. 113:26-33(2016). RN [12] RP POSSIBLE INVOLVEMENT IN SCA20. RX PubMed=18801880; DOI=10.1093/hmg/ddn283; RA Knight M.A., Hernandez D., Diede S.J., Dauwerse H.G., Rafferty I., RA van de Leemput J., Forrest S.M., Gardner R.J., Storey E., van Ommen G.J., RA Tapscott S.J., Fischbeck K.H., Singleton A.B.; RT "A duplication at chromosome 11q12.2-11q12.3 is associated with RT spinocerebellar ataxia type 20."; RL Hum. Mol. Genet. 17:3847-3853(2008). CC -!- FUNCTION: Serine hydrolase that hydrolyzes arachidonic acid-esterified CC diacylglycerols (DAGs) to produce the principal endocannabinoid, 2- CC arachidonoylglycerol (2-AG) (PubMed:14610053, PubMed:26668358, CC PubMed:23502535). Preferentially hydrolyzes sn-1 fatty acids from CC diacylglycerols (DAG) that contain arachidonic acid (AA) esterified at CC the sn-2 position to biosynthesize 2-AG (PubMed:14610053, CC PubMed:26668358, PubMed:23502535). Has negligible activity against CC other lipids including monoacylglycerols and phospholipids CC (PubMed:14610053). Plays a key role in regulating 2-AG signaling in the CC central nervous system (CNS). Regulates 2-AG involved in retrograde CC suppression at central synapses. Supports axonal growth during CC development and adult neurogenesis. Plays a role for eCB signaling in CC the physiological regulation of anxiety and depressive behaviors. CC Regulates also neuroinflammatory responses in the brain, in particular, CC LPS-induced microglial activation (By similarity). CC {ECO:0000250|UniProtKB:Q6WQJ1, ECO:0000269|PubMed:14610053, CC ECO:0000269|PubMed:23502535, ECO:0000269|PubMed:26668358}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycerol + H2O = a 2-acylglycerol + a fatty CC acid + H(+); Xref=Rhea:RHEA:33275, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17389, ChEBI:CHEBI:17815, CC ChEBI:CHEBI:28868; EC=3.1.1.116; CC Evidence={ECO:0000269|PubMed:14610053}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33276; CC Evidence={ECO:0000305|PubMed:14610053}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol CC + H2O = 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + H(+) + CC octadecanoate; Xref=Rhea:RHEA:38507, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:25629, ChEBI:CHEBI:52392, CC ChEBI:CHEBI:75728; Evidence={ECO:0000269|PubMed:14610053, CC ECO:0000269|PubMed:23502535, ECO:0000269|PubMed:26668358}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38508; CC Evidence={ECO:0000305|PubMed:14610053, ECO:0000305|PubMed:23502535, CC ECO:0000305|PubMed:26668358}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1,2-di-(9Z-octadecenoyl)-sn-glycerol + H2O = (9Z)- CC octadecenoate + 2-(9Z-octadecenoyl)-glycerol + H(+); CC Xref=Rhea:RHEA:38511, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30823, ChEBI:CHEBI:52333, ChEBI:CHEBI:73990; CC Evidence={ECO:0000269|PubMed:14610053}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38512; CC Evidence={ECO:0000305|PubMed:14610053}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-(9Z-octadecenoyl)-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn- CC glycerol + H2O = (9Z)-octadecenoate + 2-(5Z,8Z,11Z,14Z- CC eicosatetraenoyl)-glycerol + H(+); Xref=Rhea:RHEA:38515, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, CC ChEBI:CHEBI:52392, ChEBI:CHEBI:75449; CC Evidence={ECO:0000269|PubMed:14610053}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38516; CC Evidence={ECO:0000305|PubMed:14610053}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-(9Z-octadecenoyl)-2-octadecanoyl-sn-glycerol + H2O = (9Z)- CC octadecenoate + 2-octadecanoylglycerol + H(+); Xref=Rhea:RHEA:38519, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, CC ChEBI:CHEBI:75448, ChEBI:CHEBI:75456; CC Evidence={ECO:0000269|PubMed:14610053}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38520; CC Evidence={ECO:0000305|PubMed:14610053}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-(9Z-octadecenoyl)-2-(9Z,12Z-octadecadienoyl)-sn-glycerol + CC H2O = (9Z)-octadecenoate + 2-(9Z,12Z-octadecadienoyl)-glycerol + CC H(+); Xref=Rhea:RHEA:38523, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30823, ChEBI:CHEBI:75450, ChEBI:CHEBI:75457; CC Evidence={ECO:0000269|PubMed:14610053}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38524; CC Evidence={ECO:0000305|PubMed:14610053}; CC -!- CATALYTIC ACTIVITY: CC Reaction=1-(9Z-octadecenoyl)-2-O-(5Z,8Z,11Z,14Z-eicosatetraenyl)-sn- CC glycerol + H2O = (9Z)-octadecenoate + 2-O-(5Z,8Z,11Z,14Z)- CC eicosatetraenylglycerol + H(+); Xref=Rhea:RHEA:38527, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, CC ChEBI:CHEBI:75913, ChEBI:CHEBI:75914; CC Evidence={ECO:0000269|PubMed:14610053}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38528; CC Evidence={ECO:0000305|PubMed:14610053}; CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:14610053}; CC -!- ACTIVITY REGULATION: Inhibited by 1,2,3-triazole urea covalent CC inhibitors KT172, DH376 and DO34 (PubMed:26668358). Inhibited by p- CC hydroxy-mercuri-benzoate and HgCl(2), but not to PMSF. Also inhibited CC by RHC80267 (PubMed:14610053). Diacylglycerol lipase activity is CC inhibited by the phosphorylation of Ser-782 and Ser-808 by CAMK2A CC (PubMed:23502535). {ECO:0000269|PubMed:14610053, CC ECO:0000269|PubMed:23502535, ECO:0000269|PubMed:26668358}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=154.7 uM for diacylglycerol {ECO:0000269|PubMed:14610053}; CC KM=158 uM for 1-steroyl-2-arachidonoylglycerol CC {ECO:0000269|PubMed:23502535}; CC Vmax=33.3 nmol/min/mg enzyme {ECO:0000269|PubMed:14610053}; CC Vmax=9.8 pmol/min/mg enzyme with 1-steroyl-2-arachidonoylglycerol as CC substrat {ECO:0000269|PubMed:23502535}; CC pH dependence: CC Optimum pH is 7.0. {ECO:0000269|PubMed:14610053}; CC -!- SUBUNIT: Interacts (via C-terminal) with CAMK2A; leading to the CC phosphorylation and inhibition of DAGLA enzymatic activity CC (PubMed:23502535). Interacts (via PPXXF motif) with HOMER1 and HOMER2; CC this interaction is required for DAGLA membrane localization (By CC similarity). {ECO:0000250|UniProtKB:Q6WQJ1, CC ECO:0000269|PubMed:23502535}. CC -!- INTERACTION: CC Q9Y4D2; Q96FZ5: CMTM7; NbExp=3; IntAct=EBI-12808806, EBI-2807956; CC Q9Y4D2; Q8TAF8: LHFPL5; NbExp=3; IntAct=EBI-12808806, EBI-2820517; CC Q9Y4D2; P21145: MAL; NbExp=3; IntAct=EBI-12808806, EBI-3932027; CC Q9Y4D2; Q13021: MALL; NbExp=3; IntAct=EBI-12808806, EBI-750078; CC Q9Y4D2; Q5J8X5: MS4A13; NbExp=3; IntAct=EBI-12808806, EBI-12070086; CC Q9Y4D2; P27105: STOM; NbExp=3; IntAct=EBI-12808806, EBI-1211440; CC Q9Y4D2; A2RU14: TMEM218; NbExp=3; IntAct=EBI-12808806, EBI-10173151; CC Q9Y4D2; A5PKU2: TUSC5; NbExp=3; IntAct=EBI-12808806, EBI-11988865; CC Q9Y4D2; O75841: UPK1B; NbExp=6; IntAct=EBI-12808806, EBI-12237619; CC Q9Y4D2; Q3ZAQ7: VMA21; NbExp=3; IntAct=EBI-12808806, EBI-1055364; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:27595600}; CC Multi-pass membrane protein {ECO:0000255}. Postsynaptic density CC membrane {ECO:0000269|PubMed:27595600}; Multi-pass membrane protein CC {ECO:0000255}. Early endosome membrane {ECO:0000269|PubMed:27595600}; CC Multi-pass membrane protein {ECO:0000255}. Cell projection, dendritic CC spine membrane {ECO:0000250|UniProtKB:Q6WQJ1}; Multi-pass membrane CC protein {ECO:0000255}. Note=Cycles between the cell surface and an CC intracellular endosomal compartment. Internalized by early endosomes CC via a clathrin-independent pathway before transport back to the CC postsynaptic membrane surface in a PKC-dependent manner. CC {ECO:0000269|PubMed:27595600}. CC -!- TISSUE SPECIFICITY: Highly expressed in brain and pancreas. CC {ECO:0000269|PubMed:14610053, ECO:0000269|PubMed:16051747}. CC -!- PTM: Phosphorylated at Ser-782 and Ser-808 by CAMK2A; phosphorylation CC by CAMK2A inhibits diacylglycerol lipase activity. CC {ECO:0000269|PubMed:23502535}. CC -!- DISEASE: Spinocerebellar ataxia 20 (SCA20) [MIM:608687]: CC Spinocerebellar ataxia is 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. SCA20 is an autosomal dominant, adult-onset CC form characterized by dysarthria due to spasmodic dysphonia followed by CC slowly progressive ataxia. {ECO:0000269|PubMed:18801880}. Note=The CC disease may be caused by variants affecting the gene represented in CC this entry. A copy number variation consisting of a 260-kb duplication CC at chromosome 11q12.2-12.3 is responsible for SCA20. The critical gene CC within the duplicated segment may be DAGLA. CC -!- SIMILARITY: Belongs to the AB hydrolase superfamily. Lipase family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA31634.2; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY275377; AAQ17119.1; -; mRNA. DR EMBL; AB014559; BAA31634.2; ALT_INIT; mRNA. DR EMBL; AP002380; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471076; EAW73960.1; -; Genomic_DNA. DR EMBL; CH471076; EAW73961.1; -; Genomic_DNA. DR EMBL; BC150176; AAI50177.1; -; mRNA. DR EMBL; BC150195; AAI50196.1; -; mRNA. DR EMBL; BC152453; AAI52454.1; -; mRNA. DR CCDS; CCDS31578.1; -. DR PIR; T00370; T00370. DR RefSeq; NP_006124.1; NM_006133.2. DR AlphaFoldDB; Q9Y4D2; -. DR BioGRID; 107205; 20. DR IntAct; Q9Y4D2; 12. DR STRING; 9606.ENSP00000257215; -. DR BindingDB; Q9Y4D2; -. DR ChEMBL; CHEMBL5545; -. DR DrugCentral; Q9Y4D2; -. DR GuidetoPHARMACOLOGY; 1396; -. DR SwissLipids; SLP:000000323; -. DR ESTHER; human-DAGLA; Lipase_3. DR GlyCosmos; Q9Y4D2; 1 site, No reported glycans. DR GlyGen; Q9Y4D2; 1 site. DR iPTMnet; Q9Y4D2; -. DR PhosphoSitePlus; Q9Y4D2; -. DR SwissPalm; Q9Y4D2; -. DR BioMuta; DAGLA; -. DR DMDM; 114149271; -. DR jPOST; Q9Y4D2; -. DR MassIVE; Q9Y4D2; -. DR MaxQB; Q9Y4D2; -. DR PaxDb; 9606-ENSP00000257215; -. DR PeptideAtlas; Q9Y4D2; -. DR ProteomicsDB; 86167; -. DR Antibodypedia; 28260; 181 antibodies from 30 providers. DR DNASU; 747; -. DR Ensembl; ENST00000257215.10; ENSP00000257215.5; ENSG00000134780.10. DR GeneID; 747; -. DR KEGG; hsa:747; -. DR MANE-Select; ENST00000257215.10; ENSP00000257215.5; NM_006133.3; NP_006124.1. DR UCSC; uc001nsa.4; human. DR AGR; HGNC:1165; -. DR CTD; 747; -. DR DisGeNET; 747; -. DR GeneCards; DAGLA; -. DR HGNC; HGNC:1165; DAGLA. DR HPA; ENSG00000134780; Tissue enhanced (brain). DR MIM; 608687; phenotype. DR MIM; 614015; gene. DR neXtProt; NX_Q9Y4D2; -. DR OpenTargets; ENSG00000134780; -. DR PharmGKB; PA162383158; -. DR VEuPathDB; HostDB:ENSG00000134780; -. DR eggNOG; KOG2088; Eukaryota. DR GeneTree; ENSGT00940000161192; -. DR HOGENOM; CLU_008300_1_0_1; -. DR InParanoid; Q9Y4D2; -. DR OMA; YCMVAPE; -. DR OrthoDB; 373802at2759; -. DR PhylomeDB; Q9Y4D2; -. DR TreeFam; TF312928; -. DR BioCyc; MetaCyc:ENSG00000134780-MONOMER; -. DR BRENDA; 3.1.1.116; 2681. DR PathwayCommons; Q9Y4D2; -. DR Reactome; R-HSA-426048; Arachidonate production from DAG. DR SABIO-RK; Q9Y4D2; -. DR SignaLink; Q9Y4D2; -. DR SIGNOR; Q9Y4D2; -. DR BioGRID-ORCS; 747; 13 hits in 1153 CRISPR screens. DR ChiTaRS; DAGLA; human. DR GenomeRNAi; 747; -. DR Pharos; Q9Y4D2; Tchem. DR PRO; PR:Q9Y4D2; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q9Y4D2; Protein. DR Bgee; ENSG00000134780; Expressed in right frontal lobe and 110 other cell types or tissues. DR ExpressionAtlas; Q9Y4D2; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0032590; C:dendrite membrane; IDA:UniProtKB. DR GO; GO:0032591; C:dendritic spine membrane; ISS:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0098839; C:postsynaptic density membrane; IDA:UniProtKB. DR GO; GO:0045211; C:postsynaptic membrane; IBA:GO_Central. DR GO; GO:0043196; C:varicosity; IEA:Ensembl. DR GO; GO:0047372; F:acylglycerol lipase activity; TAS:Reactome. DR GO; GO:0004465; F:lipoprotein lipase activity; IBA:GO_Central. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0019369; P:arachidonic acid metabolic process; IDA:UniProtKB. DR GO; GO:1901696; P:cannabinoid biosynthetic process; IEA:Ensembl. DR GO; GO:0046340; P:diacylglycerol catabolic process; IDA:UniProtKB. DR GO; GO:0007216; P:G protein-coupled glutamate receptor signaling pathway; IEA:Ensembl. DR GO; GO:0006640; P:monoacylglycerol biosynthetic process; IEA:Ensembl. DR GO; GO:0007405; P:neuroblast proliferation; IEA:Ensembl. DR GO; GO:0150077; P:regulation of neuroinflammatory response; ISS:UniProtKB. DR GO; GO:0098921; P:retrograde trans-synaptic signaling by endocannabinoid; IMP:UniProtKB. DR CDD; cd00519; Lipase_3; 1. DR Gene3D; 3.40.50.1820; alpha/beta hydrolase; 1. DR InterPro; IPR029058; AB_hydrolase. DR InterPro; IPR002921; Fungal_lipase-like. DR PANTHER; PTHR45792; DIACYLGLYCEROL LIPASE HOMOLOG-RELATED; 1. DR PANTHER; PTHR45792:SF8; DIACYLGLYCEROL LIPASE-ALPHA; 1. DR Pfam; PF01764; Lipase_3; 1. DR SUPFAM; SSF53474; alpha/beta-Hydrolases; 1. DR PROSITE; PS00120; LIPASE_SER; 1. DR Genevisible; Q9Y4D2; HS. PE 1: Evidence at protein level; KW Calcium; Cell membrane; Cell projection; Endosome; Glycoprotein; Hydrolase; KW Lipid degradation; Lipid metabolism; Membrane; Metal-binding; KW Neurodegeneration; Phosphoprotein; Postsynaptic cell membrane; KW Reference proteome; Spinocerebellar ataxia; Synapse; Transmembrane; KW Transmembrane helix. FT CHAIN 1..1042 FT /note="Diacylglycerol lipase-alpha" FT /id="PRO_0000248347" FT TOPO_DOM 1..22 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 23..43 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 44..60 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 61..81 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 82..101 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 102..122 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 123..136 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 137..157 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 158..1042 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 846..903 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1014..1042 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1014..1029 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 472 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10037" FT ACT_SITE 524 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10037" FT MOD_RES 727 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q5YLM1" FT MOD_RES 729 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6WQJ1" FT MOD_RES 732 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6WQJ1" FT MOD_RES 743 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6WQJ1" FT MOD_RES 782 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:23502535" FT MOD_RES 784 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6WQJ1" FT MOD_RES 806 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q5YLM1" FT MOD_RES 808 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:23502535" FT MOD_RES 833 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q5YLM1" FT MOD_RES 847 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q5YLM1" FT MOD_RES 952 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6WQJ1" FT MOD_RES 1023 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q6WQJ1" FT CARBOHYD 133 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 735 FT /note="G -> V (in dbSNP:rs35056845)" FT /id="VAR_049822" FT VARIANT 889 FT /note="P -> L (in dbSNP:rs3741252)" FT /id="VAR_027274" FT VARIANT 945 FT /note="D -> E (in dbSNP:rs34956386)" FT /id="VAR_049823" FT MUTAGEN 782 FT /note="S->A: Slightly reduces phosphorylation by CAMK2A. FT Abolishes phosphorylation by CAMK2A; when associated with FT A-808." FT /evidence="ECO:0000269|PubMed:23502535" FT MUTAGEN 782 FT /note="S->E: Phosphomimetic mutation; decreased the Vmax of FT 2-AG production without affecting the KM; when associated FT with E-808." FT /evidence="ECO:0000269|PubMed:23502535" FT MUTAGEN 808 FT /note="S->A: Reduces phosphorylation by CAMK2A. Abolishes FT phosphorylation by CAMK2A; when associated with A-782." FT /evidence="ECO:0000269|PubMed:23502535" FT MUTAGEN 808 FT /note="S->E: Phosphomimetic mutation; decreased the Vmax of FT 2-AG production without affecting the KM; when associated FT with E-782." FT /evidence="ECO:0000269|PubMed:23502535" SQ SEQUENCE 1042 AA; 114952 MW; A6E675984E89CB2F CRC64; MPGIVVFRRR WSVGSDDLVL PAIFLFLLHT TWFVILSVVL FGLVYNPHEA CSLNLVDHGR GYLGILLSCM IAEMAIIWLS MRGGILYTEP RDSMQYVLYV RLAILVIEFI YAIVGIVWLT QYYTSCNDLT AKNVTLGMVV CNWVVILSVC ITVLCVFDPT GRTFVKLRAT KRRQRNLRTY NLRHRLEEGQ ATSWSRRLKV FLCCTRTKDS QSDAYSEIAY LFAEFFRDLD IVPSDIIAGL VLLRQRQRAK RNAVLDEANN DILAFLSGMP VTRNTKYLDL KNSQEMLRYK EVCYYMLFAL AAYGWPMYLM RKPACGLCQL ARSCSCCLCP ARPRFAPGVT IEEDNCCGCN AIAIRRHFLD ENMTAVDIVY TSCHDAVYET PFYVAVDHDK KKVVISIRGT LSPKDALTDL TGDAERLPVE GHHGTWLGHK GMVLSAEYIK KKLEQEMVLS QAFGRDLGRG TKHYGLIVVG HSLGAGTAAI LSFLLRPQYP TLKCFAYSPP GGLLSEDAME YSKEFVTAVV LGKDLVPRIG LSQLEGFRRQ LLDVLQRSTK PKWRIIVGAT KCIPKSELPE EVEVTTLAST RLWTHPSDLT IALSASTPLY PPGRIIHVVH NHPAEQCCCC EQEEPTYFAI WGDNKAFNEV IISPAMLHEH LPYVVMEGLN KVLENYNKGK TALLSAAKVM VSPTEVDLTP ELIFQQQPLP TGPPMPTGLA LELPTADHRN SSVRSKSQSE MSLEGFSEGR LLSPVVAAAA RQDPVELLLL STQERLAAEL QARRAPLATM ESLSDTESLY SFDSRRSSGF RSIRGSPSLH AVLERDEGHL FYIDPAIPEE NPSLSSRTEL LAADSLSKHS QDTQPLEAAL GSGGVTPERP PSAAANDEEE EVGGGGGGPA SRGELALHNG RLGDSPSPQV LEFAEFIDSL FNLDSKSSSF QDLYCMVVPE SPTSDYAEGP KSPSQQEILL RAQFEPNLVP KPPRLFAGSA DPSSGISLSP SFPLSSSGEL MDLTPTGLSS QECLAADKIR TSTPTGHGAS PAKQDELVIS AR //