Full text data of DGKA
DGKA
(DAGK, DAGK1)
[Confidence: low (only semi-automatic identification from reviews)]
Diacylglycerol kinase alpha; DAG kinase alpha; 2.7.1.107 (80 kDa diacylglycerol kinase; Diglyceride kinase alpha; DGK-alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Diacylglycerol kinase alpha; DAG kinase alpha; 2.7.1.107 (80 kDa diacylglycerol kinase; Diglyceride kinase alpha; DGK-alpha)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P23743
ID DGKA_HUMAN Reviewed; 735 AA.
AC P23743; O75481; O75482; O75483; O95217; Q3ZE25; Q8IZ56; Q8N5Q2;
read moreDT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 15-DEC-2009, sequence version 3.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Diacylglycerol kinase alpha;
DE Short=DAG kinase alpha;
DE EC=2.7.1.107;
DE AltName: Full=80 kDa diacylglycerol kinase;
DE AltName: Full=Diglyceride kinase alpha;
DE Short=DGK-alpha;
GN Name=DGKA; Synonyms=DAGK, DAGK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lymphocyte;
RX PubMed=2175712; DOI=10.1016/0014-5793(90)81461-V;
RA Schaap D., de Widt J., van der Wal J., Vandekerckhove J.,
RA van Damme J., Gussow D., Ploegh H.L., van Blitterswijk W.J.,
RA van der Bendl R.L.;
RT "Purification, cDNA-cloning and expression of human diacylglycerol
RT kinase.";
RL FEBS Lett. 275:151-158(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND ALTERNATIVE
RP SPLICING.
RC TISSUE=Uterus;
RA Champagne C.M.E., Maeda H., Takashiba S., van Dyke T.E.;
RT "Alternative splicing of diacylglycerol kinase alpha expressed in
RT human neutrophils.";
RL Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Batista E.L. Jr., Van Dyke T.E.;
RT "Characterization of a novel DGK alpha transcript generated by
RT alternative splicing.";
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP TYR-538.
RC TISSUE=Brain;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP CHROMOSOMAL LOCATION.
RX PubMed=8180475; DOI=10.1007/BF00292343;
RA Hart T.C., Champagne C., Zhou J., van Dyke T.E.;
RT "Assignment of the gene for diacylglycerol kinase (DAGK) to human
RT chromosome 12.";
RL Mamm. Genome 5:123-124(1994).
RN [7]
RP CHROMOSOMAL LOCATION.
RX PubMed=7959783; DOI=10.1006/geno.1994.1376;
RA Hart T.C., Zhou J., Champagne C., van Dyke T.E., Rao P.N.,
RA Pettenati M.J.;
RT "Assignment of the human diacylglycerol kinase gene (DAGK) to 12q13.3
RT using fluorescence in situ hybridization analysis.";
RL Genomics 22:246-247(1994).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-484, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
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.,
RA Buerckstuemmer T., 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 [10]
RP STRUCTURE BY NMR OF 1-118.
RG Northeast structural genomics consortium (NESG);
RT "NMR structure of diacylglycerol kinase alpha, NESGC target HR532.";
RL Submitted (JAN-2005) to the PDB data bank.
CC -!- FUNCTION: Upon cell stimulation converts the second messenger
CC diacylglycerol into phosphatidate, initiating the resynthesis of
CC phosphatidylinositols and attenuating protein kinase C activity.
CC -!- CATALYTIC ACTIVITY: ATP + 1,2-diacylglycerol = ADP + 1,2-diacyl-
CC sn-glycerol 3-phosphate.
CC -!- ENZYME REGULATION: Stimulated by calcium and phosphatidylserine.
CC Phosphorylated by protein kinase C.
CC -!- SUBUNIT: Monomer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P23743-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P23743-2; Sequence=VSP_032212, VSP_032213;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=3;
CC IsoId=P23743-3; Sequence=VSP_047702, VSP_047703;
CC -!- TISSUE SPECIFICITY: Lymphocytes and oligodendroglial cells.
CC -!- SIMILARITY: Belongs to the eukaryotic diacylglycerol kinase
CC family.
CC -!- SIMILARITY: Contains 1 DAGKc domain.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 2 phorbol-ester/DAG-type zinc fingers.
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DR EMBL; X62535; CAA44396.1; -; mRNA.
DR EMBL; AF064767; AAC34802.1; -; mRNA.
DR EMBL; AF064768; AAC34803.1; -; mRNA.
DR EMBL; AF064769; AAC34804.1; -; mRNA.
DR EMBL; AF064771; AAC34806.1; -; mRNA.
DR EMBL; AY930112; AAY20994.1; -; mRNA.
DR EMBL; AC025162; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC023523; AAH23523.1; -; mRNA.
DR EMBL; BC031870; AAH31870.1; -; mRNA.
DR PIR; S12969; S12969.
DR RefSeq; NP_001336.2; NM_001345.4.
DR RefSeq; NP_958852.1; NM_201444.2.
DR RefSeq; NP_958853.1; NM_201445.1.
DR RefSeq; NP_963848.1; NM_201554.1.
DR UniGene; Hs.524488; -.
DR PDB; 1TUZ; NMR; -; A=1-116.
DR PDBsum; 1TUZ; -.
DR ProteinModelPortal; P23743; -.
DR SMR; P23743; 1-198.
DR IntAct; P23743; 3.
DR MINT; MINT-8020268; -.
DR STRING; 9606.ENSP00000328405; -.
DR DrugBank; DB00163; Vitamin E.
DR PhosphoSite; P23743; -.
DR DMDM; 281185505; -.
DR PaxDb; P23743; -.
DR PRIDE; P23743; -.
DR DNASU; 1606; -.
DR Ensembl; ENST00000331886; ENSP00000328405; ENSG00000065357.
DR Ensembl; ENST00000394147; ENSP00000377703; ENSG00000065357.
DR Ensembl; ENST00000402956; ENSP00000385792; ENSG00000065357.
DR Ensembl; ENST00000548549; ENSP00000448565; ENSG00000065357.
DR Ensembl; ENST00000551156; ENSP00000450359; ENSG00000065357.
DR Ensembl; ENST00000553084; ENSP00000446605; ENSG00000065357.
DR GeneID; 1606; -.
DR KEGG; hsa:1606; -.
DR UCSC; uc001sih.1; human.
DR CTD; 1606; -.
DR GeneCards; GC12P056324; -.
DR HGNC; HGNC:2849; DGKA.
DR HPA; HPA041645; -.
DR MIM; 125855; gene.
DR neXtProt; NX_P23743; -.
DR PharmGKB; PA27310; -.
DR eggNOG; NOG47311; -.
DR HOVERGEN; HBG051345; -.
DR InParanoid; P23743; -.
DR KO; K00901; -.
DR OMA; KAQPCEV; -.
DR OrthoDB; EOG75XGK8; -.
DR PhylomeDB; P23743; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_604; Hemostasis.
DR SABIO-RK; P23743; -.
DR ChiTaRS; DGKA; human.
DR EvolutionaryTrace; P23743; -.
DR GeneWiki; DGKA; -.
DR GenomeRNAi; 1606; -.
DR NextBio; 6590; -.
DR PRO; PR:P23743; -.
DR ArrayExpress; P23743; -.
DR Bgee; P23743; -.
DR CleanEx; HS_DGKA; -.
DR Genevestigator; P23743; -.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0004143; F:diacylglycerol kinase activity; TAS:ProtInc.
DR GO; GO:0003951; F:NAD+ kinase activity; IEA:InterPro.
DR GO; GO:0005543; F:phospholipid binding; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; TAS:ProtInc.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0007205; P:protein kinase C-activating G-protein coupled receptor signaling pathway; IEA:InterPro.
DR Gene3D; 1.10.238.10; -; 1.
DR InterPro; IPR016064; ATP-NAD_kinase_PpnK-typ.
DR InterPro; IPR000756; Diacylglycerol_kin_accessory.
DR InterPro; IPR001206; Diacylglycerol_kinase_cat_dom.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR002219; Prot_Kinase_C-like_PE/DAG-bd.
DR Pfam; PF00130; C1_1; 2.
DR Pfam; PF00609; DAGK_acc; 1.
DR Pfam; PF00781; DAGK_cat; 1.
DR Pfam; PF13405; EF-hand_6; 1.
DR SMART; SM00109; C1; 2.
DR SMART; SM00045; DAGKa; 1.
DR SMART; SM00046; DAGKc; 1.
DR SMART; SM00054; EFh; 2.
DR SUPFAM; SSF111331; SSF111331; 2.
DR PROSITE; PS50146; DAGK; 1.
DR PROSITE; PS00018; EF_HAND_1; 2.
DR PROSITE; PS50222; EF_HAND_2; 2.
DR PROSITE; PS00479; ZF_DAG_PE_1; 2.
DR PROSITE; PS50081; ZF_DAG_PE_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Calcium;
KW Complete proteome; Kinase; Metal-binding; Nucleotide-binding;
KW Polymorphism; Reference proteome; Repeat; Transferase; Zinc;
KW Zinc-finger.
FT CHAIN 1 735 Diacylglycerol kinase alpha.
FT /FTId=PRO_0000218453.
FT DOMAIN 110 145 EF-hand 1.
FT DOMAIN 155 190 EF-hand 2.
FT DOMAIN 372 506 DAGKc.
FT CA_BIND 123 134 1 (Probable).
FT CA_BIND 168 179 2 (Probable).
FT ZN_FING 205 253 Phorbol-ester/DAG-type 1.
FT ZN_FING 269 319 Phorbol-ester/DAG-type 2.
FT MOD_RES 484 484 N6-acetyllysine.
FT VAR_SEQ 117 118 FT -> WS (in isoform 2).
FT /FTId=VSP_032212.
FT VAR_SEQ 119 735 Missing (in isoform 2).
FT /FTId=VSP_032213.
FT VAR_SEQ 237 247 LCKYTVHDQCA -> RPITCVGARRL (in isoform
FT 3).
FT /FTId=VSP_047702.
FT VAR_SEQ 248 735 Missing (in isoform 3).
FT /FTId=VSP_047703.
FT VARIANT 538 538 H -> Y (in dbSNP:rs17852990).
FT /FTId=VAR_031563.
FT CONFLICT 339 339 L -> P (in Ref. 2; AAC34804).
FT CONFLICT 379 379 V -> L (in Ref. 2; AAC34802).
FT CONFLICT 385 385 S -> W (in Ref. 2; AAC34802).
FT CONFLICT 684 684 E -> G (in Ref. 2; AAC34803).
FT CONFLICT 699 699 G -> V (in Ref. 1; CAA44396).
FT CONFLICT 715 715 N -> K (in Ref. 2; AAC34803).
FT HELIX 10 22
FT HELIX 27 35
FT HELIX 38 42
FT HELIX 50 60
FT HELIX 68 77
FT HELIX 96 107
SQ SEQUENCE 735 AA; 82630 MW; ACAA0AD186EE64A0 CRC64;
MAKERGLISP SDFAQLQKYM EYSTKKVSDV LKLFEDGEMA KYVQGDAIGY EGFQQFLKIY
LEVDNVPRHL SLALFQSFET GHCLNETNVT KDVVCLNDVS CYFSLLEGGR PEDKLEFTFK
LYDTDRNGIL DSSEVDKIIL QMMRVAEYLD WDVSELRPIL QEMMKEIDYD GSGSVSQAEW
VRAGATTVPL LVLLGLEMTL KDDGQHMWRP KRFPRPVYCN LCESSIGLGK QGLSCNLCKY
TVHDQCAMKA LPCEVSTYAK SRKDIGVQSH VWVRGGCESG RCDRCQKKIR IYHSLTGLHC
VWCHLEIHDD CLQAVGHECD CGLLRDHILP PSSIYPSVLA SGPDRKNSKT SQKTMDDLNL
STSEALRIDP VPNTHPLLVF VNPKSGGKQG QRVLWKFQYI LNPRQVFNLL KDGPEIGLRL
FKDVPDSRIL VCGGDGTVGW ILETIDKANL PVLPPVAVLP LGTGNDLARC LRWGGGYEGQ
NLAKILKDLE MSKVVHMDRW SVEVIPQQTE EKSDPVPFQI INNYFSIGVD ASIAHRFHIM
REKYPEKFNS RMKNKLWYFE FATSESIFST CKKLEESLTV EICGKPLDLS NLSLEGIAVL
NIPSMHGGSN LWGDTRRPHG DIYGINQALG ATAKVITDPD ILKTCVPDLS DKRLEVVGLE
GAIEMGQIYT KLKNAGRRLA KCSEITFHTT KTLPMQIDGE PWMQTPCTIK ITHKNQMPML
MGPPPRSTNF FGFLS
//
ID DGKA_HUMAN Reviewed; 735 AA.
AC P23743; O75481; O75482; O75483; O95217; Q3ZE25; Q8IZ56; Q8N5Q2;
read moreDT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 15-DEC-2009, sequence version 3.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Diacylglycerol kinase alpha;
DE Short=DAG kinase alpha;
DE EC=2.7.1.107;
DE AltName: Full=80 kDa diacylglycerol kinase;
DE AltName: Full=Diglyceride kinase alpha;
DE Short=DGK-alpha;
GN Name=DGKA; Synonyms=DAGK, DAGK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lymphocyte;
RX PubMed=2175712; DOI=10.1016/0014-5793(90)81461-V;
RA Schaap D., de Widt J., van der Wal J., Vandekerckhove J.,
RA van Damme J., Gussow D., Ploegh H.L., van Blitterswijk W.J.,
RA van der Bendl R.L.;
RT "Purification, cDNA-cloning and expression of human diacylglycerol
RT kinase.";
RL FEBS Lett. 275:151-158(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND ALTERNATIVE
RP SPLICING.
RC TISSUE=Uterus;
RA Champagne C.M.E., Maeda H., Takashiba S., van Dyke T.E.;
RT "Alternative splicing of diacylglycerol kinase alpha expressed in
RT human neutrophils.";
RL Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Batista E.L. Jr., Van Dyke T.E.;
RT "Characterization of a novel DGK alpha transcript generated by
RT alternative splicing.";
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP TYR-538.
RC TISSUE=Brain;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP CHROMOSOMAL LOCATION.
RX PubMed=8180475; DOI=10.1007/BF00292343;
RA Hart T.C., Champagne C., Zhou J., van Dyke T.E.;
RT "Assignment of the gene for diacylglycerol kinase (DAGK) to human
RT chromosome 12.";
RL Mamm. Genome 5:123-124(1994).
RN [7]
RP CHROMOSOMAL LOCATION.
RX PubMed=7959783; DOI=10.1006/geno.1994.1376;
RA Hart T.C., Zhou J., Champagne C., van Dyke T.E., Rao P.N.,
RA Pettenati M.J.;
RT "Assignment of the human diacylglycerol kinase gene (DAGK) to 12q13.3
RT using fluorescence in situ hybridization analysis.";
RL Genomics 22:246-247(1994).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-484, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
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.,
RA Buerckstuemmer T., 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 [10]
RP STRUCTURE BY NMR OF 1-118.
RG Northeast structural genomics consortium (NESG);
RT "NMR structure of diacylglycerol kinase alpha, NESGC target HR532.";
RL Submitted (JAN-2005) to the PDB data bank.
CC -!- FUNCTION: Upon cell stimulation converts the second messenger
CC diacylglycerol into phosphatidate, initiating the resynthesis of
CC phosphatidylinositols and attenuating protein kinase C activity.
CC -!- CATALYTIC ACTIVITY: ATP + 1,2-diacylglycerol = ADP + 1,2-diacyl-
CC sn-glycerol 3-phosphate.
CC -!- ENZYME REGULATION: Stimulated by calcium and phosphatidylserine.
CC Phosphorylated by protein kinase C.
CC -!- SUBUNIT: Monomer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P23743-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P23743-2; Sequence=VSP_032212, VSP_032213;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=3;
CC IsoId=P23743-3; Sequence=VSP_047702, VSP_047703;
CC -!- TISSUE SPECIFICITY: Lymphocytes and oligodendroglial cells.
CC -!- SIMILARITY: Belongs to the eukaryotic diacylglycerol kinase
CC family.
CC -!- SIMILARITY: Contains 1 DAGKc domain.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 2 phorbol-ester/DAG-type zinc fingers.
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; X62535; CAA44396.1; -; mRNA.
DR EMBL; AF064767; AAC34802.1; -; mRNA.
DR EMBL; AF064768; AAC34803.1; -; mRNA.
DR EMBL; AF064769; AAC34804.1; -; mRNA.
DR EMBL; AF064771; AAC34806.1; -; mRNA.
DR EMBL; AY930112; AAY20994.1; -; mRNA.
DR EMBL; AC025162; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC023523; AAH23523.1; -; mRNA.
DR EMBL; BC031870; AAH31870.1; -; mRNA.
DR PIR; S12969; S12969.
DR RefSeq; NP_001336.2; NM_001345.4.
DR RefSeq; NP_958852.1; NM_201444.2.
DR RefSeq; NP_958853.1; NM_201445.1.
DR RefSeq; NP_963848.1; NM_201554.1.
DR UniGene; Hs.524488; -.
DR PDB; 1TUZ; NMR; -; A=1-116.
DR PDBsum; 1TUZ; -.
DR ProteinModelPortal; P23743; -.
DR SMR; P23743; 1-198.
DR IntAct; P23743; 3.
DR MINT; MINT-8020268; -.
DR STRING; 9606.ENSP00000328405; -.
DR DrugBank; DB00163; Vitamin E.
DR PhosphoSite; P23743; -.
DR DMDM; 281185505; -.
DR PaxDb; P23743; -.
DR PRIDE; P23743; -.
DR DNASU; 1606; -.
DR Ensembl; ENST00000331886; ENSP00000328405; ENSG00000065357.
DR Ensembl; ENST00000394147; ENSP00000377703; ENSG00000065357.
DR Ensembl; ENST00000402956; ENSP00000385792; ENSG00000065357.
DR Ensembl; ENST00000548549; ENSP00000448565; ENSG00000065357.
DR Ensembl; ENST00000551156; ENSP00000450359; ENSG00000065357.
DR Ensembl; ENST00000553084; ENSP00000446605; ENSG00000065357.
DR GeneID; 1606; -.
DR KEGG; hsa:1606; -.
DR UCSC; uc001sih.1; human.
DR CTD; 1606; -.
DR GeneCards; GC12P056324; -.
DR HGNC; HGNC:2849; DGKA.
DR HPA; HPA041645; -.
DR MIM; 125855; gene.
DR neXtProt; NX_P23743; -.
DR PharmGKB; PA27310; -.
DR eggNOG; NOG47311; -.
DR HOVERGEN; HBG051345; -.
DR InParanoid; P23743; -.
DR KO; K00901; -.
DR OMA; KAQPCEV; -.
DR OrthoDB; EOG75XGK8; -.
DR PhylomeDB; P23743; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_604; Hemostasis.
DR SABIO-RK; P23743; -.
DR ChiTaRS; DGKA; human.
DR EvolutionaryTrace; P23743; -.
DR GeneWiki; DGKA; -.
DR GenomeRNAi; 1606; -.
DR NextBio; 6590; -.
DR PRO; PR:P23743; -.
DR ArrayExpress; P23743; -.
DR Bgee; P23743; -.
DR CleanEx; HS_DGKA; -.
DR Genevestigator; P23743; -.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0004143; F:diacylglycerol kinase activity; TAS:ProtInc.
DR GO; GO:0003951; F:NAD+ kinase activity; IEA:InterPro.
DR GO; GO:0005543; F:phospholipid binding; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; TAS:ProtInc.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0007205; P:protein kinase C-activating G-protein coupled receptor signaling pathway; IEA:InterPro.
DR Gene3D; 1.10.238.10; -; 1.
DR InterPro; IPR016064; ATP-NAD_kinase_PpnK-typ.
DR InterPro; IPR000756; Diacylglycerol_kin_accessory.
DR InterPro; IPR001206; Diacylglycerol_kinase_cat_dom.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR002219; Prot_Kinase_C-like_PE/DAG-bd.
DR Pfam; PF00130; C1_1; 2.
DR Pfam; PF00609; DAGK_acc; 1.
DR Pfam; PF00781; DAGK_cat; 1.
DR Pfam; PF13405; EF-hand_6; 1.
DR SMART; SM00109; C1; 2.
DR SMART; SM00045; DAGKa; 1.
DR SMART; SM00046; DAGKc; 1.
DR SMART; SM00054; EFh; 2.
DR SUPFAM; SSF111331; SSF111331; 2.
DR PROSITE; PS50146; DAGK; 1.
DR PROSITE; PS00018; EF_HAND_1; 2.
DR PROSITE; PS50222; EF_HAND_2; 2.
DR PROSITE; PS00479; ZF_DAG_PE_1; 2.
DR PROSITE; PS50081; ZF_DAG_PE_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Calcium;
KW Complete proteome; Kinase; Metal-binding; Nucleotide-binding;
KW Polymorphism; Reference proteome; Repeat; Transferase; Zinc;
KW Zinc-finger.
FT CHAIN 1 735 Diacylglycerol kinase alpha.
FT /FTId=PRO_0000218453.
FT DOMAIN 110 145 EF-hand 1.
FT DOMAIN 155 190 EF-hand 2.
FT DOMAIN 372 506 DAGKc.
FT CA_BIND 123 134 1 (Probable).
FT CA_BIND 168 179 2 (Probable).
FT ZN_FING 205 253 Phorbol-ester/DAG-type 1.
FT ZN_FING 269 319 Phorbol-ester/DAG-type 2.
FT MOD_RES 484 484 N6-acetyllysine.
FT VAR_SEQ 117 118 FT -> WS (in isoform 2).
FT /FTId=VSP_032212.
FT VAR_SEQ 119 735 Missing (in isoform 2).
FT /FTId=VSP_032213.
FT VAR_SEQ 237 247 LCKYTVHDQCA -> RPITCVGARRL (in isoform
FT 3).
FT /FTId=VSP_047702.
FT VAR_SEQ 248 735 Missing (in isoform 3).
FT /FTId=VSP_047703.
FT VARIANT 538 538 H -> Y (in dbSNP:rs17852990).
FT /FTId=VAR_031563.
FT CONFLICT 339 339 L -> P (in Ref. 2; AAC34804).
FT CONFLICT 379 379 V -> L (in Ref. 2; AAC34802).
FT CONFLICT 385 385 S -> W (in Ref. 2; AAC34802).
FT CONFLICT 684 684 E -> G (in Ref. 2; AAC34803).
FT CONFLICT 699 699 G -> V (in Ref. 1; CAA44396).
FT CONFLICT 715 715 N -> K (in Ref. 2; AAC34803).
FT HELIX 10 22
FT HELIX 27 35
FT HELIX 38 42
FT HELIX 50 60
FT HELIX 68 77
FT HELIX 96 107
SQ SEQUENCE 735 AA; 82630 MW; ACAA0AD186EE64A0 CRC64;
MAKERGLISP SDFAQLQKYM EYSTKKVSDV LKLFEDGEMA KYVQGDAIGY EGFQQFLKIY
LEVDNVPRHL SLALFQSFET GHCLNETNVT KDVVCLNDVS CYFSLLEGGR PEDKLEFTFK
LYDTDRNGIL DSSEVDKIIL QMMRVAEYLD WDVSELRPIL QEMMKEIDYD GSGSVSQAEW
VRAGATTVPL LVLLGLEMTL KDDGQHMWRP KRFPRPVYCN LCESSIGLGK QGLSCNLCKY
TVHDQCAMKA LPCEVSTYAK SRKDIGVQSH VWVRGGCESG RCDRCQKKIR IYHSLTGLHC
VWCHLEIHDD CLQAVGHECD CGLLRDHILP PSSIYPSVLA SGPDRKNSKT SQKTMDDLNL
STSEALRIDP VPNTHPLLVF VNPKSGGKQG QRVLWKFQYI LNPRQVFNLL KDGPEIGLRL
FKDVPDSRIL VCGGDGTVGW ILETIDKANL PVLPPVAVLP LGTGNDLARC LRWGGGYEGQ
NLAKILKDLE MSKVVHMDRW SVEVIPQQTE EKSDPVPFQI INNYFSIGVD ASIAHRFHIM
REKYPEKFNS RMKNKLWYFE FATSESIFST CKKLEESLTV EICGKPLDLS NLSLEGIAVL
NIPSMHGGSN LWGDTRRPHG DIYGINQALG ATAKVITDPD ILKTCVPDLS DKRLEVVGLE
GAIEMGQIYT KLKNAGRRLA KCSEITFHTT KTLPMQIDGE PWMQTPCTIK ITHKNQMPML
MGPPPRSTNF FGFLS
//
MIM
125855
*RECORD*
*FIELD* NO
125855
*FIELD* TI
*125855 DIACYLGLYCEROL KINASE, ALPHA, 80-KD; DGKA
;;DIACYLGLYCEROL KINASE, ALPHA; DAGK1;;
read moreDAGK, 80-KD;;
DGK-ALPHA
*FIELD* TX
DESCRIPTION
Diacylglycerol (DAG) kinases (DGKs or DAGKs; EC 2.7.1.107), such as
DGKA, phosphorylate DAG to phosphatidic acid, thus removing DAG.
Phosphatidic acid functions both in signaling and phospholipid
synthesis. In intracellular signaling pathways, DAGK can be viewed as a
modulator that competes with protein kinase C (PKC; see 600448) for the
second messenger DAG (summary by Topham and Prescott, 1999).
CLONING
By sequencing tryptic peptides of DG kinase purified from human white
blood cells, followed by PCR of human Jurkat leukemic T cells and
screening human DND41 leukemic T cells, Schaap et al. (1990) obtained
full-length DAGK cDNA. The deduced 735-amino acid protein has a
calculated molecular mass of 82.7 kD. It has 2 EF-hand motifs predicted
to bind calcium, 2 cysteine-repeat regions, 2 putative ATP-binding
sites, and a C-terminal stretch of 110 amino acids that is fully
conserved between human and pig DAGK. One of the ATP-binding sites is
contained within the first cysteine-rich region. Northern blot analysis
detected a 3.2-kb DAGK transcript in Jurkat cells and in normal human T
cells. Purified human DAGK had an apparent molecular mass of 86 kD by
SDS-PAGE and 87 kD by gel filtration.
GENE FUNCTION
Schaap et al. (1990) found that DAGK purified from human white blood
cells showed optimal activity in the presence of phosphatidylserine and
deoxycholate. It showed relatively broad specificity, and DAG analogs
containing an unsaturated fatty acid at the sn-2 position gave optimal
enzymatic activity in the presence or absence of deoxycholate. Activity
was not altered by calcium or calcium chelation. COS-7 cells
overexpressing human DAGK showed 6- to 7-fold higher DAGK activity than
controls.
Several mammalian isozymes of DAGK have been identified. The isoform
described by Schaap et al. (1990) has been designated DGK-alpha or
DAGK1. Topham and Prescott (1999) stated that all DGKs have a conserved
catalytic domain and at least 2 cysteine-rich regions homologous to the
C1A and C1B motifs of PKCs. Most DGKs have structural motifs that are
likely to play regulatory roles, and these motifs form the basis for
dividing the DGKs into 5 subtypes. Type I DGKs, such as DGK-alpha, -beta
(604070), and -gamma (601854), have calcium-binding EF-hand motifs at
their N termini. DGK-delta (601826) and DKG-eta (604071) contain
N-terminal pleckstrin homology (PH) domains and are defined as type II.
DGK-epsilon (601440) contains no identifiable regulatory domains and is
a type III DGK. The defining characteristic of type IV isozymes, such as
DGK-zeta (601441) and -iota (604072), is that they have C-terminal
ankyrin repeats. Group V is exemplified by DGK-theta (601207), which
contains 3 cysteine-rich domains and a PH domain.
Pilz et al. (1995) pointed to the growing evidence to support some form
of light-activated phosphoinositide signal transduction pathway in the
mammalian retina. Although this pathway had no obvious role in mammalian
phototransduction, mutations in this pathway were known to cause retinal
degeneration in Drosophila. For example, the 'retinal degeneration A'
mutant in Drosophila is caused by an alteration in the eye-specific DAGK
gene.
To maintain cellular homeostasis, intracellular DAG levels must be
tightly regulated. DAG functions in intracellular signaling pathways as
an allosteric activator of PKC. In addition, DAG appears to play a role
in regulating RAS (see 190020) and RHO (see 165370) family proteins by
activating the guanine nucleotide exchange factors VAV (164875) and
RASGRP1 (603962). DAG also occupies a central position in the synthesis
of major phospholipids and triacylglycerols. Topham and Prescott (1999)
summarized the roles of mammalian DAGKs.
Seven-transmembrane receptor signaling is transduced by second
messengers such as DAG generated in response to the heterotrimeric
guanine nucleotide-binding protein G(q) (600998) and is terminated by
receptor desensitization and degradation of the second messengers.
Nelson et al. (2007) showed that beta-arrestins (see 107940) coordinate
both processes for the G(q)-coupled M1 muscarinic receptor (CHRM1;
118510). Beta-arrestins physically interact with diacylglycerol kinases,
enzymes that degrade DAG. Moreover, beta-arrestins are essential for
conversion of DAG to phosphatidic acid after agonist stimulation, and
this activity requires recruitment of the beta-arrestin-DGK complex to
activated 7-transmembrane receptors. The dual function of
beta-arrestins, limiting production of diacylglycerol (by receptor
desensitization) while enhancing its rate of degradation, is analogous
to their ability to recruit adenosine 3-prime,5-prime-monophosphate
phosphodiesterases to G(s) (139320)-coupled beta-2-adrenergic receptors
(ADRB2; 109690). Thus, Nelson et al. (2007) concluded that
beta-arrestins can serve similar regulatory functions for disparate
classes of 7-transmembrane receptors through structurally dissimilar
enzymes that degrade chemically distinct second messengers.
BIOCHEMICAL FEATURES
- Solution Structure
Van Horn et al. (2009) solved the solution structure of prokaryotic Dagk
solubilized in dodecylphosphocholine micelles. The 121-amino acid Dagk
subunits formed homotrimers in solution, and each subunit contributed 3
transmembrane helices to the holoenzyme. The structure suggested domain
swapping between Dagk monomers, where transmembrane helix 3 of each
subunit interacted with transmembrane helices 1 and 2 from an adjacent
subunit, stabilizing the structure.
- Crystal Structure
Li et al. (2013) presented the crystal structure for 3 functional forms
of the 121-amino acid prokaryotic diacylglycerol kinase subunit, one of
which was wildtype. The structure revealed a homotrimeric enzyme with 3
transmembrane helices and an amino-terminal amphiphilic helix per
monomer. Bound lipid substrate and docked ATP identified the putative
active site that is of the composite, shared site type. The crystal
structures rationalized extensive biochemical and biophysical data on
the enzyme. They were, however, at variance with the solution NMR model
of van Horn et al. (2009) in that domain swapping, a key feature of the
solution form, was not observed in the crystal structures.
MAPPING
In an effort to consider genes mutated in Drosophila as candidates for
mammalian eye disease, Pilz et al. (1995) determined the map position of
3 DAGK genes in the mouse. They localized the mouse homolog of DAGK1 to
chromosome 10 by linkage analysis.
By Southern blot analysis of human-hamster somatic cell hybrid DNA, Hart
et al. (1994) assigned the DAGK gene to chromosome 12. Hart et al.
(1994) further localized the gene to 12q13.3 by fluorescence in situ
hybridization.
*FIELD* RF
1. Hart, T. C.; Champagne, C.; Zhou, J.; Van Dyke, T. E.: Assignment
of the gene for diacylglycerol kinase (DAGK) to human chromosome 12. Mammalian
Genome 5: 123-124, 1994.
2. Hart, T. C.; Zhou, J.; Champagne, C.; Van Dyke, T. E.; Rao, P.
N.; Pettenati, M. J.: Assignment of the human diacylglycerol kinase
gene (DAGK) to 12q13.3 using fluorescence in situ hybridization analysis. Genomics 22:
246-247, 1994.
3. Li, D.; Lyons, J. A.; Pye, V. E.; Vogeley, L.; Aragao, D.; Kenyohn,
C. P.; Shah, S. T. A.; Doherty, C.; Aherne, M.; Caffrey, M.: Crystal
structure of the integral membrane diacylglycerol kinase. Nature 497:
521-524, 2013.
4. Nelson, C. D.; Perry, S. J.; Regier, D. S.; Prescott, S. M.; Topham,
M. K.; Lefkowitz, R. J.: Targeting of diacylglycerol degradation
to M1 muscarinic receptors by beta-arrestins. Science 315: 663-666,
2007.
5. Pilz, A.; Schaap, D.; Hunt, D.; Fitzgibbon, J.: Chromosomal localization
of three mouse diacylglycerol kinase (DAGK) genes: genes sharing sequence
homology to the Drosophila retinal degeneration A (rdgA) gene. Genomics 26:
599-601, 1995.
6. Schaap, D.; de Widt, J.; van der Wal, J.; Vandekerckhove, J.; van
Damme, J.; Gussow, D.; Ploegh, H. L.; van Blitterswijk, W. J.; van
der Bend, R. L.: Purification, cDNA-cloning and expression of human
diacylglycerol kinase. FEBS Lett. 275: 151-158, 1990.
7. Topham, M. K.; Prescott, S. M.: Mammalian diacylglycerol kinases,
a family of lipid kinases with signaling functions. J. Biol. Chem. 274:
11447-11450, 1999.
8. Van Horn, W. D.; Kim, H.-J.; Ellis, C. D.; Hadziselimovic, A.;
Sulistijo, E. S.; Karra, M. D.; Tian, C.; Sonnichsen, F. D.; Sanders,
C. R.: Solution nuclear magnetic resonance structure of membrane-integral
diacylglycerol kinase. Science 324: 1726-1729, 2009.
*FIELD* CN
Ada Hamosh - updated: 7/10/2013
Ada Hamosh - updated: 5/1/2007
Rebekah S. Rasooly - updated: 7/28/1999
Lori M. Kelman - updated: 9/24/1996
*FIELD* CD
Victor A. McKusick: 2/5/1993
*FIELD* ED
alopez: 07/19/2013
alopez: 7/10/2013
alopez: 5/1/2007
carol: 1/5/2000
mgross: 7/28/1999
mgross: 3/16/1999
alopez: 10/16/1998
alopez: 6/24/1997
alopez: 6/10/1997
jamie: 10/23/1996
jamie: 10/16/1996
mark: 10/2/1996
mark: 9/24/1996
terry: 9/24/1996
mark: 9/24/1996
mark: 4/17/1996
terry: 4/10/1996
mark: 5/16/1995
carol: 10/7/1994
carol: 2/5/1993
*RECORD*
*FIELD* NO
125855
*FIELD* TI
*125855 DIACYLGLYCEROL KINASE, ALPHA, 80-KD; DGKA
;;DIACYLGLYCEROL KINASE, ALPHA; DAGK1;;
read moreDAGK, 80-KD;;
DGK-ALPHA
*FIELD* TX
DESCRIPTION
Diacylglycerol (DAG) kinases (DGKs or DAGKs; EC 2.7.1.107), such as
DGKA, phosphorylate DAG to phosphatidic acid, thus removing DAG.
Phosphatidic acid functions both in signaling and phospholipid
synthesis. In intracellular signaling pathways, DAGK can be viewed as a
modulator that competes with protein kinase C (PKC; see 600448) for the
second messenger DAG (summary by Topham and Prescott, 1999).
CLONING
By sequencing tryptic peptides of DG kinase purified from human white
blood cells, followed by PCR of human Jurkat leukemic T cells and
screening human DND41 leukemic T cells, Schaap et al. (1990) obtained
full-length DAGK cDNA. The deduced 735-amino acid protein has a
calculated molecular mass of 82.7 kD. It has 2 EF-hand motifs predicted
to bind calcium, 2 cysteine-repeat regions, 2 putative ATP-binding
sites, and a C-terminal stretch of 110 amino acids that is fully
conserved between human and pig DAGK. One of the ATP-binding sites is
contained within the first cysteine-rich region. Northern blot analysis
detected a 3.2-kb DAGK transcript in Jurkat cells and in normal human T
cells. Purified human DAGK had an apparent molecular mass of 86 kD by
SDS-PAGE and 87 kD by gel filtration.
GENE FUNCTION
Schaap et al. (1990) found that DAGK purified from human white blood
cells showed optimal activity in the presence of phosphatidylserine and
deoxycholate. It showed relatively broad specificity, and DAG analogs
containing an unsaturated fatty acid at the sn-2 position gave optimal
enzymatic activity in the presence or absence of deoxycholate. Activity
was not altered by calcium or calcium chelation. COS-7 cells
overexpressing human DAGK showed 6- to 7-fold higher DAGK activity than
controls.
Several mammalian isozymes of DAGK have been identified. The isoform
described by Schaap et al. (1990) has been designated DGK-alpha or
DAGK1. Topham and Prescott (1999) stated that all DGKs have a conserved
catalytic domain and at least 2 cysteine-rich regions homologous to the
C1A and C1B motifs of PKCs. Most DGKs have structural motifs that are
likely to play regulatory roles, and these motifs form the basis for
dividing the DGKs into 5 subtypes. Type I DGKs, such as DGK-alpha, -beta
(604070), and -gamma (601854), have calcium-binding EF-hand motifs at
their N termini. DGK-delta (601826) and DKG-eta (604071) contain
N-terminal pleckstrin homology (PH) domains and are defined as type II.
DGK-epsilon (601440) contains no identifiable regulatory domains and is
a type III DGK. The defining characteristic of type IV isozymes, such as
DGK-zeta (601441) and -iota (604072), is that they have C-terminal
ankyrin repeats. Group V is exemplified by DGK-theta (601207), which
contains 3 cysteine-rich domains and a PH domain.
Pilz et al. (1995) pointed to the growing evidence to support some form
of light-activated phosphoinositide signal transduction pathway in the
mammalian retina. Although this pathway had no obvious role in mammalian
phototransduction, mutations in this pathway were known to cause retinal
degeneration in Drosophila. For example, the 'retinal degeneration A'
mutant in Drosophila is caused by an alteration in the eye-specific DAGK
gene.
To maintain cellular homeostasis, intracellular DAG levels must be
tightly regulated. DAG functions in intracellular signaling pathways as
an allosteric activator of PKC. In addition, DAG appears to play a role
in regulating RAS (see 190020) and RHO (see 165370) family proteins by
activating the guanine nucleotide exchange factors VAV (164875) and
RASGRP1 (603962). DAG also occupies a central position in the synthesis
of major phospholipids and triacylglycerols. Topham and Prescott (1999)
summarized the roles of mammalian DAGKs.
Seven-transmembrane receptor signaling is transduced by second
messengers such as DAG generated in response to the heterotrimeric
guanine nucleotide-binding protein G(q) (600998) and is terminated by
receptor desensitization and degradation of the second messengers.
Nelson et al. (2007) showed that beta-arrestins (see 107940) coordinate
both processes for the G(q)-coupled M1 muscarinic receptor (CHRM1;
118510). Beta-arrestins physically interact with diacylglycerol kinases,
enzymes that degrade DAG. Moreover, beta-arrestins are essential for
conversion of DAG to phosphatidic acid after agonist stimulation, and
this activity requires recruitment of the beta-arrestin-DGK complex to
activated 7-transmembrane receptors. The dual function of
beta-arrestins, limiting production of diacylglycerol (by receptor
desensitization) while enhancing its rate of degradation, is analogous
to their ability to recruit adenosine 3-prime,5-prime-monophosphate
phosphodiesterases to G(s) (139320)-coupled beta-2-adrenergic receptors
(ADRB2; 109690). Thus, Nelson et al. (2007) concluded that
beta-arrestins can serve similar regulatory functions for disparate
classes of 7-transmembrane receptors through structurally dissimilar
enzymes that degrade chemically distinct second messengers.
BIOCHEMICAL FEATURES
- Solution Structure
Van Horn et al. (2009) solved the solution structure of prokaryotic Dagk
solubilized in dodecylphosphocholine micelles. The 121-amino acid Dagk
subunits formed homotrimers in solution, and each subunit contributed 3
transmembrane helices to the holoenzyme. The structure suggested domain
swapping between Dagk monomers, where transmembrane helix 3 of each
subunit interacted with transmembrane helices 1 and 2 from an adjacent
subunit, stabilizing the structure.
- Crystal Structure
Li et al. (2013) presented the crystal structure for 3 functional forms
of the 121-amino acid prokaryotic diacylglycerol kinase subunit, one of
which was wildtype. The structure revealed a homotrimeric enzyme with 3
transmembrane helices and an amino-terminal amphiphilic helix per
monomer. Bound lipid substrate and docked ATP identified the putative
active site that is of the composite, shared site type. The crystal
structures rationalized extensive biochemical and biophysical data on
the enzyme. They were, however, at variance with the solution NMR model
of van Horn et al. (2009) in that domain swapping, a key feature of the
solution form, was not observed in the crystal structures.
MAPPING
In an effort to consider genes mutated in Drosophila as candidates for
mammalian eye disease, Pilz et al. (1995) determined the map position of
3 DAGK genes in the mouse. They localized the mouse homolog of DAGK1 to
chromosome 10 by linkage analysis.
By Southern blot analysis of human-hamster somatic cell hybrid DNA, Hart
et al. (1994) assigned the DAGK gene to chromosome 12. Hart et al.
(1994) further localized the gene to 12q13.3 by fluorescence in situ
hybridization.
*FIELD* RF
1. Hart, T. C.; Champagne, C.; Zhou, J.; Van Dyke, T. E.: Assignment
of the gene for diacylglycerol kinase (DAGK) to human chromosome 12. Mammalian
Genome 5: 123-124, 1994.
2. Hart, T. C.; Zhou, J.; Champagne, C.; Van Dyke, T. E.; Rao, P.
N.; Pettenati, M. J.: Assignment of the human diacylglycerol kinase
gene (DAGK) to 12q13.3 using fluorescence in situ hybridization analysis. Genomics 22:
246-247, 1994.
3. Li, D.; Lyons, J. A.; Pye, V. E.; Vogeley, L.; Aragao, D.; Kenyohn,
C. P.; Shah, S. T. A.; Doherty, C.; Aherne, M.; Caffrey, M.: Crystal
structure of the integral membrane diacylglycerol kinase. Nature 497:
521-524, 2013.
4. Nelson, C. D.; Perry, S. J.; Regier, D. S.; Prescott, S. M.; Topham,
M. K.; Lefkowitz, R. J.: Targeting of diacylglycerol degradation
to M1 muscarinic receptors by beta-arrestins. Science 315: 663-666,
2007.
5. Pilz, A.; Schaap, D.; Hunt, D.; Fitzgibbon, J.: Chromosomal localization
of three mouse diacylglycerol kinase (DAGK) genes: genes sharing sequence
homology to the Drosophila retinal degeneration A (rdgA) gene. Genomics 26:
599-601, 1995.
6. Schaap, D.; de Widt, J.; van der Wal, J.; Vandekerckhove, J.; van
Damme, J.; Gussow, D.; Ploegh, H. L.; van Blitterswijk, W. J.; van
der Bend, R. L.: Purification, cDNA-cloning and expression of human
diacylglycerol kinase. FEBS Lett. 275: 151-158, 1990.
7. Topham, M. K.; Prescott, S. M.: Mammalian diacylglycerol kinases,
a family of lipid kinases with signaling functions. J. Biol. Chem. 274:
11447-11450, 1999.
8. Van Horn, W. D.; Kim, H.-J.; Ellis, C. D.; Hadziselimovic, A.;
Sulistijo, E. S.; Karra, M. D.; Tian, C.; Sonnichsen, F. D.; Sanders,
C. R.: Solution nuclear magnetic resonance structure of membrane-integral
diacylglycerol kinase. Science 324: 1726-1729, 2009.
*FIELD* CN
Ada Hamosh - updated: 7/10/2013
Ada Hamosh - updated: 5/1/2007
Rebekah S. Rasooly - updated: 7/28/1999
Lori M. Kelman - updated: 9/24/1996
*FIELD* CD
Victor A. McKusick: 2/5/1993
*FIELD* ED
alopez: 07/19/2013
alopez: 7/10/2013
alopez: 5/1/2007
carol: 1/5/2000
mgross: 7/28/1999
mgross: 3/16/1999
alopez: 10/16/1998
alopez: 6/24/1997
alopez: 6/10/1997
jamie: 10/23/1996
jamie: 10/16/1996
mark: 10/2/1996
mark: 9/24/1996
terry: 9/24/1996
mark: 9/24/1996
mark: 4/17/1996
terry: 4/10/1996
mark: 5/16/1995
carol: 10/7/1994
carol: 2/5/1993