CGAS_MOUSE
ID CGAS_MOUSE Reviewed; 507 AA.
AC Q8C6L5; Q3ULW3;
DT 06-MAR-2013, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=Cyclic GMP-AMP synthase {ECO:0000303|PubMed:23258413};
DE Short=cGAMP synthase {ECO:0000303|PubMed:23258413};
DE Short=cGAS {ECO:0000303|PubMed:23258413};
DE Short=m-cGAS {ECO:0000303|PubMed:23258413};
DE EC=2.7.7.86 {ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:28963528, ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:30007416};
DE AltName: Full=2'3'-cGAMP synthase {ECO:0000303|PubMed:23258413};
DE AltName: Full=Mab-21 domain-containing protein 1 {ECO:0000305};
GN Name=Cgas {ECO:0000303|PubMed:23258413, ECO:0000312|MGI:MGI:2442261};
GN Synonyms=Mb21d1 {ECO:0000312|MGI:MGI:2442261};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, DNA-BINDING, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF GLU-211 AND ASP-213.
RX PubMed=23258413; DOI=10.1126/science.1232458;
RA Sun L., Wu J., Du F., Chen X., Chen Z.J.;
RT "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type
RT I interferon pathway.";
RL Science 339:786-791(2013).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Mammary gland, and Ovary;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Limb;
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 [6]
RP FUNCTION.
RX PubMed=23722158; DOI=10.1038/nature12306;
RA Ablasser A., Goldeck M., Cavlar T., Deimling T., Witte G., Rohl I.,
RA Hopfner K.P., Ludwig J., Hornung V.;
RT "cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that
RT activates STING.";
RL Nature 498:380-384(2013).
RN [7]
RP FUNCTION.
RX PubMed=24077100; DOI=10.1038/nature12640;
RA Ablasser A., Schmid-Burgk J.L., Hemmerling I., Horvath G.L., Schmidt T.,
RA Latz E., Hornung V.;
RT "Cell intrinsic immunity spreads to bystander cells via the intercellular
RT transfer of cGAMP.";
RL Nature 503:530-534(2013).
RN [8]
RP FUNCTION.
RX PubMed=23929945; DOI=10.1126/science.1240933;
RA Gao D., Wu J., Wu Y.T., Du F., Aroh C., Yan N., Sun L., Chen Z.J.;
RT "Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other
RT retroviruses.";
RL Science 341:903-906(2013).
RN [9]
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=25525874; DOI=10.1016/j.cell.2014.11.036;
RA White M.J., McArthur K., Metcalf D., Lane R.M., Cambier J.C., Herold M.J.,
RA van Delft M.F., Bedoui S., Lessene G., Ritchie M.E., Huang D.C., Kile B.T.;
RT "Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN
RT production.";
RL Cell 159:1549-1562(2014).
RN [10]
RP PHOSPHORYLATION AT SER-291, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP SER-291.
RX PubMed=26440888; DOI=10.1016/j.celrep.2015.09.007;
RA Seo G.J., Yang A., Tan B., Kim S., Liang Q., Choi Y., Yuan W., Feng P.,
RA Park H.S., Jung J.U.;
RT "Akt kinase-mediated checkpoint of cGAS DNA sensing pathway.";
RL Cell Rep. 13:440-449(2015).
RN [11]
RP FUNCTION, AND MUTAGENESIS OF GLY-198 AND SER-199.
RX PubMed=26229117; DOI=10.1126/science.aab3632;
RA Bridgeman A., Maelfait J., Davenne T., Partridge T., Peng Y., Mayer A.,
RA Dong T., Kaever V., Borrow P., Rehwinkel J.;
RT "Viruses transfer the antiviral second messenger cGAMP between cells.";
RL Science 349:1228-1232(2015).
RN [12]
RP SUMOYLATION AT LYS-217 AND LYS-464, UBIQUITINATION AT LYS-271 AND LYS-464,
RP AND MUTAGENESIS OF LYS-217; LYS-271; LYS-335 AND LYS-464.
RX PubMed=27637147; DOI=10.1016/j.immuni.2016.08.014;
RA Hu M.M., Yang Q., Xie X.Q., Liao C.Y., Lin H., Liu T.T., Yin L., Shu H.B.;
RT "Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor
RT STING to regulate the kinetics of response to DNA virus.";
RL Immunity 45:555-569(2016).
RN [13]
RP GLUTAMYLATION AT GLU-272, GLUTAMYLATION AT GLU-302, AND MUTAGENESIS OF
RP GLU-272 AND GLU-302.
RX PubMed=26829768; DOI=10.1038/ni.3356;
RA Xia P., Ye B., Wang S., Zhu X., Du Y., Xiong Z., Tian Y., Fan Z.;
RT "Glutamylation of the DNA sensor cGAS regulates its binding and synthase
RT activity in antiviral immunity.";
RL Nat. Immunol. 17:369-378(2016).
RN [14]
RP FUNCTION, DOMAIN, MONOMER, AND DNA-BINDING.
RX PubMed=28214358; DOI=10.1002/1873-3468.12598;
RA Lee A., Park E.B., Lee J., Choi B.S., Kang S.J.;
RT "The N terminus of cGAS de-oligomerizes the cGAS:DNA complex and lifts the
RT DNA size restriction of core-cGAS activity.";
RL FEBS Lett. 591:954-961(2017).
RN [15]
RP FUNCTION, DOMAIN, CLEAVAGE, AND ACTIVITY REGULATION.
RX PubMed=28314590; DOI=10.1016/j.immuni.2017.02.011;
RA Wang Y., Ning X., Gao P., Wu S., Sha M., Lv M., Zhou X., Gao J., Fang R.,
RA Meng G., Su X., Jiang Z.;
RT "Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to
RT regulate responses to DNA virus infection.";
RL Immunity 46:393-404(2017).
RN [16]
RP FUNCTION, DNA-BINDING, AND DOMAIN.
RX PubMed=28363908; DOI=10.4049/jimmunol.1601909;
RA Tao J., Zhang X.W., Jin J., Du X.X., Lian T., Yang J., Zhou X., Jiang Z.,
RA Su X.D.;
RT "Nonspecific DNA Binding of cGAS N Terminus Promotes cGAS Activation.";
RL J. Immunol. 198:3627-3636(2017).
RN [17]
RP FUNCTION.
RX PubMed=28738408; DOI=10.1038/nature23449;
RA Mackenzie K.J., Carroll P., Martin C.A., Murina O., Fluteau A.,
RA Simpson D.J., Olova N., Sutcliffe H., Rainger J.K., Leitch A., Osborn R.T.,
RA Wheeler A.P., Nowotny M., Gilbert N., Chandra T., Reijns M.A.M.,
RA Jackson A.P.;
RT "cGAS surveillance of micronuclei links genome instability to innate
RT immunity.";
RL Nature 548:461-465(2017).
RN [18]
RP FUNCTION.
RX PubMed=28759028; DOI=10.1038/ncb3586;
RA Glueck S., Guey B., Gulen M.F., Wolter K., Kang T.W., Schmacke N.A.,
RA Bridgeman A., Rehwinkel J., Zender L., Ablasser A.;
RT "Innate immune sensing of cytosolic chromatin fragments through cGAS
RT promotes senescence.";
RL Nat. Cell Biol. 19:1061-1070(2017).
RN [19]
RP SUMOYLATION AT LYS-335; LYS-372 AND LYS-382, DESUMOYLATION BY SENP7,
RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF LYS-335; LYS-372 AND
RP LYS-382.
RX PubMed=28095500; DOI=10.1371/journal.ppat.1006156;
RA Cui Y., Yu H., Zheng X., Peng R., Wang Q., Zhou Y., Wang R., Wang J.,
RA Qu B., Shen N., Guo Q., Liu X., Wang C.;
RT "SENP7 potentiates cGAS activation by relieving SUMO-mediated inhibition of
RT cytosolic DNA sensing.";
RL PLoS Pathog. 13:e1006156-e1006156(2017).
RN [20]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF ASN-172;
RP ARG-180; CYS-419 AND HIS-467.
RX PubMed=30007416; DOI=10.1016/j.cell.2018.06.026;
RA Zhou W., Whiteley A.T., de Oliveira Mann C.C., Morehouse B.R., Nowak R.P.,
RA Fischer E.S., Gray N.S., Mekalanos J.J., Kranzusch P.J.;
RT "Structure of the human cGAS-DNA complex reveals enhanced control of immune
RT surveillance.";
RL Cell 174:300-311(2018).
RN [21]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=29625897; DOI=10.1016/j.immuni.2018.03.016;
RA Xia P., Wang S., Ye B., Du Y., Li C., Xiong Z., Qu Y., Fan Z.;
RT "A circular RNA protects dormant hematopoietic stem cells from DNA sensor
RT cGAS-mediated exhaustion.";
RL Immunity 48:688-701(2018).
RN [22]
RP FUNCTION.
RX PubMed=30356214; DOI=10.1038/s41586-018-0629-6;
RA Liu H., Zhang H., Wu X., Ma D., Wu J., Wang L., Jiang Y., Fei Y., Zhu C.,
RA Tan R., Jungblut P., Pei G., Dorhoi A., Yan Q., Zhang F., Zheng R., Liu S.,
RA Liang H., Liu Z., Yang H., Chen J., Wang P., Tang T., Peng W., Hu Z.,
RA Xu Z., Huang X., Wang J., Li H., Zhou Y., Liu F., Yan D., Kaufmann S.H.E.,
RA Chen C., Mao Z., Ge B.;
RT "Nuclear cGAS suppresses DNA repair and promotes tumorigenesis.";
RL Nature 563:131-136(2018).
RN [23]
RP UBIQUITINATION AT LYS-335, FUNCTION, SUBUNIT, ACTIVITY REGULATION, AND
RP MUTAGENESIS OF LYS-278; LYS-335 AND LYS-350.
RX PubMed=29426904; DOI=10.1038/s41467-018-02936-3;
RA Seo G.J., Kim C., Shin W.J., Sklan E.H., Eoh H., Jung J.U.;
RT "TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing.";
RL Nat. Commun. 9:613-613(2018).
RN [24]
RP CATALYTIC ACTIVITY, AND COFACTOR.
RX PubMed=29976794; DOI=10.1126/science.aat1022;
RA Du M., Chen Z.J.;
RT "DNA-induced liquid phase condensation of cGAS activates innate immune
RT signaling.";
RL Science 361:704-709(2018).
RN [25]
RP SUBCELLULAR LOCATION, AND LIPID-BINDING.
RX PubMed=30827685; DOI=10.1016/j.cell.2019.01.049;
RA Barnett K.C., Coronas-Serna J.M., Zhou W., Ernandes M.J., Cao A.,
RA Kranzusch P.J., Kagan J.C.;
RT "Phosphoinositide interactions position cGAS at the plasma membrane to
RT ensure efficient distinction between self- and viral DNA.";
RL Cell 176:1432-1446(2019).
RN [26]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 211-GLU--ASP-213;
RP ARG-222; LYS-240; ARG-241; 242-ILE--PRO-247; ARG-244; LYS-335; LYS-382;
RP GLU-386 AND 395-LYS--LYS-399.
RX PubMed=31808743; DOI=10.7554/elife.47491;
RA Volkman H.E., Cambier S., Gray E.E., Stetson D.B.;
RT "Tight nuclear tethering of cGAS is essential for preventing
RT autoreactivity.";
RL Elife 8:0-0(2019).
RN [27]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=31544964; DOI=10.15252/embj.2019102718;
RA Jiang H., Xue X., Panda S., Kawale A., Hooy R.M., Liang F., Sohn J.,
RA Sung P., Gekara N.O.;
RT "Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates
RT genome destabilization and cell death.";
RL EMBO J. 38:e102718-e102718(2019).
RN [28]
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=30878284; DOI=10.1016/j.molcel.2019.02.013;
RA Ning X., Wang Y., Jing M., Sha M., Lv M., Gao P., Zhang R., Huang X.,
RA Feng J.M., Jiang Z.;
RT "Apoptotic caspases suppress type i interferon production via the cleavage
RT of cGAS, MAVS, and IRF3.";
RL Mol. Cell 74:19-31(2019).
RN [29]
RP PHOSPHORYLATION AT SER-291.
RX PubMed=32351706; DOI=10.1038/s41421-020-0162-2;
RA Zhong L., Hu M.M., Bian L.J., Liu Y., Chen Q., Shu H.B.;
RT "Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis.";
RL Cell Discov. 6:26-26(2020).
RN [30]
RP UBIQUITINATION AT LYS-271 AND LYS-464, DEUBIQUITINATION, AND MUTAGENESIS OF
RP LYS-271 AND LYS-464.
RX PubMed=32457395; DOI=10.1038/s41422-020-0341-6;
RA Zhang Q., Tang Z., An R., Ye L., Zhong B.;
RT "USP29 maintains the stability of cGAS and promotes cellular antiviral
RT responses and autoimmunity.";
RL Cell Res. 30:914-927(2020).
RN [31]
RP DEUBIQUITINATION.
RX PubMed=31534008; DOI=10.4049/jimmunol.1900514;
RA Guo Y., Jiang F., Kong L., Li B., Yang Y., Zhang L., Liu B., Zheng Y.,
RA Gao C.;
RT "USP27X deubiquitinates and stabilizes the DNA sensor cGAS to regulate
RT cytosolic DNA-mediated signaling.";
RL J. Immunol. 203:2049-2054(2019).
RN [32]
RP ACTIVITY REGULATION.
RX PubMed=32156810; DOI=10.1128/mbio.00136-20;
RA Ma H., Qian W., Bambouskova M., Collins P.L., Porter S.I., Byrum A.K.,
RA Zhang R., Artyomov M., Oltz E.M., Mosammaparast N., Miner J.J.,
RA Diamond M.S.;
RT "Barrier-to-autointegration factor 1 protects against a basal cGAS-STING
RT response.";
RL MBio 11:0-0(2020).
RN [33]
RP PHOSPHORYLATION AT SER-420, DEPHOSPHORYLATION, ACTIVITY REGULATION, AND
RP MUTAGENESIS OF SER-420.
RX PubMed=32474700; DOI=10.1007/s13238-020-00729-3;
RA Li M., Shu H.B.;
RT "Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity
RT and innate antiviral response.";
RL Protein Cell 11:584-599(2020).
RN [34]
RP FUNCTION.
RX PubMed=33688080; DOI=10.1126/scisignal.aax7942;
RA Apel F., Andreeva L., Knackstedt L.S., Streeck R., Frese C.K., Goosmann C.,
RA Hopfner K.P., Zychlinsky A.;
RT "The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps.";
RL Sci. Signal. 14:0-0(2021).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 147-507 IN COMPLEXES WITH DNA;
RP GMP; GTP; ATP; CYCLIC GMP-AMP; MAGNESIUM AND ZINC IONS, FUNCTION, COFACTOR,
RP CATALYTIC ACTIVITY, AND DNA-BINDING.
RX PubMed=23647843; DOI=10.1016/j.cell.2013.04.046;
RA Gao P., Ascano M., Wu Y., Barchet W., Gaffney B.L., Zillinger T.,
RA Serganov A.A., Liu Y., Jones R.A., Hartmann G., Tuschl T., Patel D.J.;
RT "Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by
RT DNA-activated cyclic GMP-AMP synthase.";
RL Cell 153:1094-1107(2013).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.36 ANGSTROMS) OF 142-507 IN COMPLEX WITH
RP 2',3'-CGAMP AND ZINC, AND DOMAIN.
RX PubMed=24332030; DOI=10.1016/j.immuni.2013.10.019;
RA Li X., Shu C., Yi G., Chaton C.T., Shelton C.L., Diao J., Zuo X., Kao C.C.,
RA Herr A.B., Li P.;
RT "Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced
RT oligomerization.";
RL Immunity 39:1019-1031(2013).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF 147-507 IN COMPLEX WITH ZINC, AND
RP SUBUNIT.
RX PubMed=24462292; DOI=10.1016/j.celrep.2014.01.003;
RA Zhang X., Wu J., Du F., Xu H., Sun L., Chen Z., Brautigam C.A., Zhang X.,
RA Chen Z.J.;
RT "The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and
RT undergoes switch-like conformational changes in the activation loop.";
RL Cell Rep. 6:421-430(2014).
RN [38] {ECO:0007744|PDB:5N6I}
RP X-RAY CRYSTALLOGRAPHY (3.60 ANGSTROMS) OF 139-507 IN COMPLEX WITH ZINC AND
RP DNA, FUNCTION, AND SUBUNIT.
RX PubMed=28902841; DOI=10.1038/nature23890;
RA Andreeva L., Hiller B., Kostrewa D., Lassig C., de Oliveira Mann C.C.,
RA Jan Drexler D., Maiser A., Gaidt M., Leonhardt H., Hornung V.,
RA Hopfner K.P.;
RT "cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA
RT ladders.";
RL Nature 549:394-398(2017).
RN [39] {ECO:0007744|PDB:5XZB, ECO:0007744|PDB:5XZE, ECO:0007744|PDB:5XZG}
RP X-RAY CRYSTALLOGRAPHY (1.83 ANGSTROMS) OF 147-507 IN COMPLEX WITH ZINC AND
RP INHIBITOR RU.521, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=28963528; DOI=10.1038/s41467-017-00833-9;
RA Vincent J., Adura C., Gao P., Luz A., Lama L., Asano Y., Okamoto R.,
RA Imaeda T., Aida J., Rothamel K., Gogakos T., Steinberg J., Reasoner S.,
RA Aso K., Tuschl T., Patel D.J., Glickman J.F., Ascano M.;
RT "Small molecule inhibition of cGAS reduces interferon expression in primary
RT macrophages from autoimmune mice.";
RL Nat. Commun. 8:750-750(2017).
RN [40] {ECO:0007744|PDB:7BUJ, ECO:0007744|PDB:7BUM, ECO:0007744|PDB:7BUQ}
RP X-RAY CRYSTALLOGRAPHY (2.13 ANGSTROMS) OF 61-507 IN COMPLEX WITH ZINC,
RP FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR.
RX PubMed=32814054; DOI=10.1016/j.celrep.2020.108053;
RA Zhao Z., Ma Z., Wang B., Guan Y., Su X.D., Jiang Z.;
RT "Mn2+ directly activates cGAS and structural analysis suggests Mn2+ Induces
RT a noncanonical catalytic synthesis of 2'3'-cGAMP.";
RL Cell Rep. 32:108053-108053(2020).
RN [41] {ECO:0007744|PDB:6X59, ECO:0007744|PDB:6X5A, ECO:0007744|PDB:6XJD}
RP STRUCTURE BY ELECTRON MICROSCOPY (2.98 ANGSTROMS) OF 142-507 IN COMPLEX
RP WITH NUCLEOSOME CORE AND ZINC, COFACTOR, FUNCTION, INTERACTION WITH
RP NUCLEOSOMES, ACTIVITY REGULATION, SUBCELLULAR LOCATION, DOMAIN, AND
RP MUTAGENESIS OF ARG-222; LYS-238; LYS-240; ARG-241; ARG-244; LYS-315;
RP LYS-323; LYS-335; ARG-341; ARG-342 AND LYS-382.
RX PubMed=32911481; DOI=10.1038/s41586-020-2749-z;
RA Zhao B., Xu P., Rowlett C.M., Jing T., Shinde O., Lei Y., West A.P.,
RA Liu W.R., Li P.;
RT "The molecular basis of tight nuclear tethering and inactivation of cGAS.";
RL Nature 587:673-677(2020).
RN [42] {ECO:0007744|PDB:7A08}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.11 ANGSTROMS) OF 139-507 IN COMPLEX
RP WITH NUCLEOSOME CORE AND ZINC, COFACTOR, FUNCTION, INTERACTION WITH
RP NUCLEOSOMES, ACTIVITY REGULATION, SUBCELLULAR LOCATION, DOMAIN, AND
RP MUTAGENESIS OF ARG-222; LYS-240; ARG-241; ARG-337; ARG-341 AND ARG-342.
RX PubMed=32911480; DOI=10.1038/s41586-020-2748-0;
RA Michalski S., de Oliveira Mann C.C., Stafford C.A., Witte G., Bartho J.,
RA Lammens K., Hornung V., Hopfner K.P.;
RT "Structural basis for sequestration and autoinhibition of cGAS by
RT chromatin.";
RL Nature 587:678-682(2020).
RN [43] {ECO:0007744|PDB:7JO9, ECO:0007744|PDB:7JOA}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.30 ANGSTROMS) OF 142-507 IN COMPLEX
RP WITH NUCLEOSOME AND ZINC, COFACTOR, FUNCTION, INTERACTION WITH NUCLEOSOMES,
RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF
RP ARG-222; LYS-240 AND ARG-241.
RX PubMed=32913000; DOI=10.1126/science.abd0609;
RA Boyer J.A., Spangler C.J., Strauss J.D., Cesmat A.P., Liu P., McGinty R.K.,
RA Zhang Q.;
RT "Structural basis of nucleosome-dependent cGAS inhibition.";
RL Science 370:450-454(2020).
CC -!- FUNCTION: Nucleotidyltransferase that catalyzes the formation of cyclic
CC GMP-AMP (2',3'-cGAMP) from ATP and GTP and plays a key role in innate
CC immunity (PubMed:23258413, PubMed:23647843, PubMed:23722158,
CC PubMed:26829768, PubMed:28214358, PubMed:29625897, PubMed:29426904,
CC PubMed:32814054). Catalysis involves both the formation of a 2',5'
CC phosphodiester linkage at the GpA step and the formation of a 3',5'
CC phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p]
CC (PubMed:23258413, PubMed:23647843, PubMed:23722158, PubMed:26829768,
CC PubMed:28214358). Acts as a key DNA sensor: directly binds double-
CC stranded DNA (dsDNA), inducing the formation of liquid-like droplets in
CC which CGAS is activated, leading to synthesis of 2',3'-cGAMP, a second
CC messenger that binds to and activates STING1, thereby triggering type-I
CC interferon production (PubMed:23722158, PubMed:28314590,
CC PubMed:28363908, PubMed:28095500). Preferentially binds long dsDNA
CC (around 45 bp) and forms ladder-like networks that function
CC cooperatively to stabilize individual cGAS-dsDNA complexes
CC (PubMed:28902841). Acts as a key foreign DNA sensor, the presence of
CC double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that
CC triggers the immune responses (PubMed:23722158, PubMed:28314590,
CC PubMed:28363908). Has antiviral activity by sensing the presence of
CC dsDNA from DNA viruses in the cytoplasm (PubMed:23258413,
CC PubMed:23722158, PubMed:23647843). Also acts as an innate immune sensor
CC of infection by retroviruses by detecting the presence of reverse-
CC transcribed DNA in the cytosol (PubMed:23929945). Detection of
CC retroviral reverse-transcribed DNA in the cytosol may be indirect and
CC be mediated via interaction with PQBP1, which directly binds reverse-
CC transcribed retroviral DNA (By similarity). Also detects the presence
CC of DNA from bacteria (By similarity). 2',3'-cGAMP can be transferred
CC from producing cells to neighboring cells through gap junctions,
CC leading to promote STING1 activation and convey immune response to
CC connecting cells (PubMed:24077100). 2',3'-cGAMP can also be transferred
CC between cells by virtue of packaging within viral particles
CC contributing to IFN-induction in newly infected cells in a cGAS-
CC independent but STING1-dependent manner (PubMed:26229117). Also senses
CC the presence of neutrophil extracellular traps (NETs) that are
CC translocated to the cytosol following phagocytosis, leading to
CC synthesis of 2',3'-cGAMP (PubMed:33688080). In addition to foreign DNA,
CC can also be activated by endogenous nuclear or mitochondrial DNA (By
CC similarity). When self-DNA leaks into the cytosol during cellular
CC stress (such as mitochondrial stress, DNA damage, mitotic arrest or
CC senescence), or is present in form of cytosolic micronuclei, CGAS is
CC activated leading to a state of sterile inflammation (PubMed:28738408,
CC PubMed:28759028). Acts as a regulator of cellular senescence by binding
CC to cytosolic chromatin fragments that are present in senescent cells,
CC leading to trigger type-I interferon production via STING1 and promote
CC cellular senescence (PubMed:28759028). Also involved in the
CC inflammatory response to genome instability and double-stranded DNA
CC breaks: acts by localizing to micronuclei arising from genome
CC instability (PubMed:28738408). Micronuclei, which as frequently found
CC in cancer cells, consist of chromatin surrounded by its own nuclear
CC membrane: following breakdown of the micronuclear envelope, a process
CC associated with chromothripsis, CGAS binds self-DNA exposed to the
CC cytosol, leading to 2',3'-cGAMP synthesis and subsequent activation of
CC STING1 and type-I interferon production (PubMed:28738408). In a healthy
CC cell, CGAS is however kept inactive even in cellular events that
CC directly expose it to self-DNA, such as mitosis, when cGAS associates
CC with chromatin directly after nuclear envelope breakdown or remains in
CC the form of postmitotic persistent nuclear cGAS pools bound to
CC chromatin (By similarity). Nuclear CGAS is inactivated by chromatin via
CC direct interaction with nucleosomes, which block CGAS from DNA binding
CC and thus prevent CGAS-induced autoimmunity (PubMed:31808743,
CC PubMed:32911481, PubMed:32911480, PubMed:32913000). Also acts as a
CC suppressor of DNA repair in response to DNA damage: inhibits homologous
CC recombination repair by interacting with PARP1, the CGAS-PARP1
CC interaction leading to impede the formation of the PARP1-TIMELESS
CC complex (PubMed:30356214, PubMed:31544964). In addition to DNA, also
CC sense translation stress: in response to translation stress,
CC translocates to the cytosol and associates with collided ribosomes,
CC promoting its activation and triggering type-I interferon production
CC (By similarity). {ECO:0000250|UniProtKB:Q8N884,
CC ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:23647843,
CC ECO:0000269|PubMed:23722158, ECO:0000269|PubMed:23929945,
CC ECO:0000269|PubMed:24077100, ECO:0000269|PubMed:26229117,
CC ECO:0000269|PubMed:26829768, ECO:0000269|PubMed:28095500,
CC ECO:0000269|PubMed:28214358, ECO:0000269|PubMed:28314590,
CC ECO:0000269|PubMed:28363908, ECO:0000269|PubMed:28738408,
CC ECO:0000269|PubMed:28759028, ECO:0000269|PubMed:28902841,
CC ECO:0000269|PubMed:29426904, ECO:0000269|PubMed:29625897,
CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:31544964,
CC ECO:0000269|PubMed:31808743, ECO:0000269|PubMed:32814054,
CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
CC ECO:0000269|PubMed:32913000, ECO:0000269|PubMed:33688080}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + GTP = 2',3'-cGAMP + 2 diphosphate; Xref=Rhea:RHEA:42064,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:143093; EC=2.7.7.86;
CC Evidence={ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:28963528,
CC ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:30007416,
CC ECO:0000269|PubMed:32814054};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42065;
CC Evidence={ECO:0000269|PubMed:23258413};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:23647843};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:32814054};
CC Note=Binds 1 Mg(2+) per subunit (PubMed:23647843). Is also active with
CC Mn(2+) (PubMed:23647843, PubMed:32814054). Mn(2+)-activated enyzme
CC forms an inverted pppGp(2'-5')A intermediate, suggesting a non-
CC canonical but accelerated 2',3'-cGAMP cyclization without substrate
CC flip-over (PubMed:32814054). Mn(2+) ions are coordinated by
CC triphosphate moiety of the inverted substrate, independent of the
CC catalytic triad residues (PubMed:32814054).
CC {ECO:0000269|PubMed:23647843, ECO:0000269|PubMed:32814054};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:32814054,
CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
CC ECO:0000269|PubMed:32913000};
CC Note=Undergoes a liquid-like phase transition after binding to DNA,
CC which is dependent on zinc. {ECO:0000250|UniProtKB:Q8N884};
CC -!- ACTIVITY REGULATION: The enzyme activity is strongly increased by
CC double-stranded DNA (dsDNA), but not by single-stranded DNA or RNA (By
CC similarity). DNA-binding induces the formation of liquid-like droplets
CC in which CGAS is activated (By similarity). Liquid-like droplets also
CC create a selective environment that restricts entry of negative
CC regulators, such as TREX1 or BANF1/BAF, allowing sensing of DNA (By
CC similarity). A number of mechanisms exist to restrict its activity
CC toward self-DNA (PubMed:32911481, PubMed:32911480, PubMed:32913000).
CC The nucleotidyltransferase activity is inhibited in the nucleus via its
CC association with nucleosomes: interacts with the acidic patch of
CC histones H2A and H2B, thereby blocking DNA-binding and subsequent
CC activation (PubMed:32156810, PubMed:32911481, PubMed:32911480,
CC PubMed:32913000). CGAS is also inactive when associated with mitotic
CC chromatin (By similarity). Chromatin-bound CGAS cannot be activated by
CC exogenous DNA in mitotic cells: phosphorylation of the N-terminal
CC disordered part by AURKB during the G2-M transition blocks CGAS liquid
CC phase separation and activation (By similarity). Activity toward self-
CC DNA is inhibited by BANF1/BAF upon acute loss of nuclear membrane
CC integrity: BANF1/BAF acts by outcompeting CGAS for DNA-binding, thereby
CC preventing CGAS activation (PubMed:32156810). DNA-induced activation at
CC micronuclei is also limited by TREX1, which degrades micronuclear DNA
CC upon nuclear envelope rupture, thereby preventing CGAS activation (By
CC similarity). Acetylation at Lys-372, Lys-382 and Lys-402 inhibits the
CC cyclic GMP-AMP synthase activity (By similarity). Acetylation by KAT5
CC increases the cyclic GMP-AMP synthase activity by promoting DNA-binding
CC and subsequent activation (By similarity). Phosphorylation at Ser-291
CC suppresses the nucleotidyltransferase activity (PubMed:26440888).
CC Phosphorylation at Ser-420 promotes the cyclic GMP-AMP synthase
CC activity (PubMed:32474700). Phosphorylation at Thr-52 and Ser-199
CC inhibits its cyclic GMP-AMP synthase activity (By similarity).
CC Ubiquitination at Lys-372 via 'Lys-27'-linked polyubiquitination
CC enhances the cyclic GMP-AMP synthase activity (By similarity).
CC Monoubiquitination at Lys-335 promotes oligomerization and subsequent
CC activation (PubMed:29426904). Sumoylation at Lys-335, Lys-372 and Lys-
CC 382 prevents DNA-binding, oligomerization and nucleotidyltransferase
CC activity (PubMed:28095500). The enzyme activity is impaired by the
CC cleavage by CASP1 (PubMed:28314590). In addition to DNA, also activated
CC by collided ribosomes upon translation stress: specifically binds
CC collided ribosomes, promoting its activation and triggering type-I
CC interferon production (By similarity). In hematopoietic stem cells,
CC binding to circular RNA cia-cGAS inhibits the cyclic GMP-AMP synthase
CC activity (PubMed:29625897). Strongly inhibited by compound RU.521,
CC which is specific for mouse protein (PubMed:28963528, PubMed:30007416).
CC {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:26440888,
CC ECO:0000269|PubMed:28095500, ECO:0000269|PubMed:28314590,
CC ECO:0000269|PubMed:28963528, ECO:0000269|PubMed:29426904,
CC ECO:0000269|PubMed:29625897, ECO:0000269|PubMed:30007416,
CC ECO:0000269|PubMed:32156810, ECO:0000269|PubMed:32474700,
CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
CC ECO:0000269|PubMed:32913000}.
CC -!- SUBUNIT: Monomer in the absence of DNA (PubMed:28214358). Homodimer in
CC presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two
CC DNA molecules (PubMed:29426904, PubMed:28902841). Interacts with
CC nucleosomes; interaction is mainly mediated via histones H2A and H2B
CC and inactivates the nucleotidyltransferase activity by blocking DNA-
CC binding and subsequent activation (PubMed:32911481, PubMed:32911480,
CC PubMed:32913000). Interacts with PQBP1 (via WW domain) (By similarity).
CC Interacts with TRIM14; this interaction recruits USP14, leading to
CC deubiquitinate and stabilize CGAS and promote type I interferon
CC production (By similarity). Interacts with ZCCHC3; promoting sensing of
CC dsDNA by CGAS (By similarity). Interacts with PARP1; interaction takes
CC place in the nucleus and prevents the formation of the PARP1-TIMELESS
CC complex (By similarity). {ECO:0000250|UniProtKB:Q8N884,
CC ECO:0000269|PubMed:28214358, ECO:0000269|PubMed:28902841,
CC ECO:0000269|PubMed:29426904, ECO:0000269|PubMed:32911480,
CC ECO:0000269|PubMed:32911481, ECO:0000269|PubMed:32913000}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:31544964,
CC ECO:0000269|PubMed:31808743}. Chromosome {ECO:0000269|PubMed:31544964,
CC ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
CC ECO:0000269|PubMed:32913000}. Cell membrane
CC {ECO:0000269|PubMed:30827685}; Peripheral membrane protein
CC {ECO:0000269|PubMed:30827685}. Cytoplasm, cytosol
CC {ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:31544964,
CC ECO:0000269|PubMed:31808743}. Note=Mainly localizes in the nucleus, and
CC at low level in the cytosol (PubMed:31808743, PubMed:31544964). On
CC chromosomes, enriched on centromeric satellite and LINE DNA repeat
CC elements (By similarity). Exported from the nucleus to the cytosol in a
CC XPO1/CRM1 via the nuclear export signal in response to DNA stimulation
CC (By similarity). Outside the nucleus, localizes at the cell membrane as
CC a peripheral membrane protein in resting conditions: association to the
CC cell membrane is mediated via binding to phosphatidylinositol 4,5-
CC bisphosphate (PtdIns(4,5)P2) (PubMed:30827685). Localization at the
CC cell membrane is required to limit the recognition of self-DNA (By
CC similarity). Following detection of double-stranded DNA (dsDNA),
CC released from the cell membrane into the cytosol in order to signal (By
CC similarity). Upon transfection with dsDNA forms punctate structures
CC that co-localize with DNA and Beclin-1 (BECN1) (By similarity).
CC Phosphorylation at Tyr-201 promotes cytosolic retention (By
CC similarity). In response to translation stress, translocates to the
CC cytosol and associates with collided ribosomes (By similarity).
CC {ECO:0000250|UniProtKB:Q8N884, ECO:0000269|PubMed:30827685,
CC ECO:0000269|PubMed:31544964, ECO:0000269|PubMed:31808743}.
CC -!- DOMAIN: The N-terminal disordered part (1-146) binds unspecifically
CC dsDNA and expand the binding and moving range of CGAS on dsDNA
CC (PubMed:28214358, PubMed:28314590, PubMed:28363908). The disordered and
CC positively charged residues enhance CGAS-DNA phase separation by
CC increasing the valencies of DNA-binding (By similarity). The N-terminus
CC is required to sense chromatin and its phosphorylation blocks its
CC activation by chromatin DNA (By similarity). When the N-terminal part
CC (1-146) is missing the protein bound to dsDNA homodimerizes
CC (PubMed:28214358). {ECO:0000250|UniProtKB:Q8N884,
CC ECO:0000269|PubMed:28214358, ECO:0000269|PubMed:28314590,
CC ECO:0000269|PubMed:28363908}.
CC -!- DOMAIN: The arginine-anchor tightly binds to the canonical H2A acidic-
CC patch residues. {ECO:0000269|PubMed:32911480,
CC ECO:0000269|PubMed:32911481, ECO:0000269|PubMed:32913000}.
CC -!- PTM: The N-terminal disordered part (1-146) is phosphorylated by AURKB
CC during the G2-M transition, blocking CGAS liquid phase separation and
CC preventing activation (By similarity). Phosphorylation at Tyr-201 by
CC BLK promotes cytosolic retention (By similarity). Localizes into the
CC nucleus following dephosphorylation at Tyr-201 (By similarity).
CC Phosphorylation at Ser-420 activates the nucleotidyltransferase
CC activity (PubMed:32474700). Dephosphorylation at Ser-420 by PPP6C
CC impairs its ability to bind GTP, thereby inactivating it
CC (PubMed:32474700). Phosphorylation at Thr-52 and Ser-199 by PRKDC
CC inhibits its cyclic GMP-AMP synthase activity by impairing
CC homodimerization and activation (By similarity). Phosphorylation at
CC Ser-291 by AKT (AKT1, AKT2 or AKT3) suppresses the
CC nucleotidyltransferase activity (PubMed:26440888). Phosphorylation at
CC Ser-291 by CDK1 during mitosis leads to its inhibition, thereby
CC preventing CGAS activation by self-DNA during mitosis
CC (PubMed:32351706). Dephosphorylated at Ser-291 by protein phosphatase
CC PP1 upon mitotic exit (PubMed:32351706). {ECO:0000250|UniProtKB:Q8N884,
CC ECO:0000269|PubMed:26440888, ECO:0000269|PubMed:32351706,
CC ECO:0000269|PubMed:32474700}.
CC -!- PTM: Ubiquitinated at Lys-402 via 'Lys-48'-linked polyubiquitin chains,
CC leading to its SQSTM1-mediated autophagic degradation (By similarity).
CC Interaction with TRIM14 promotes recruitment of USP14, leading to
CC deubiquitinate Lys-402 and stabilize CGAS (By similarity).
CC Ubiquitinated at Lys-372 by RNF185 via 'Lys-27'-linked
CC polyubiquitination, promoting CGAS cyclic GMP-AMP synthase activity (By
CC similarity). Monoubiquitination at Lys-335 by TRIM56 promotes
CC oligomerization and subsequent activation (PubMed:29426904).
CC Monoubiquitination by TRIM41 promotes CGAS activation (By similarity).
CC Ubiquitination at Lys-271 and Lys-464 via 'Lys-48'-linked
CC polyubiquitination promotes its degradation (PubMed:32457395,
CC PubMed:27637147). Deubiquitination at Lys-271 by USP29 promotes its
CC stabilization (PubMed:32457395). Deubiquitinated by USP27X, promoting
CC its stabilization (PubMed:31534008). {ECO:0000250|UniProtKB:Q8N884,
CC ECO:0000269|PubMed:27637147, ECO:0000269|PubMed:29426904,
CC ECO:0000269|PubMed:31534008, ECO:0000269|PubMed:32457395}.
CC -!- PTM: Sumoylated at Lys-217 and Lys-464 by TRIM38 in uninfected cells
CC and during the early phase of viral infection, promoting its stability
CC by preventing ubiquitination at Lys-271 and Lys-464, and subsequent
CC degradation (PubMed:27637147). Desumoylated by SENP2 during the late
CC phase of viral infection (PubMed:27637147). Sumoylation at Lys-335,
CC Lys-372 and Lys-382 prevents DNA-binding, oligomerization and
CC nucleotidyltransferase activity (PubMed:28095500). Desumoylation at
CC Lys-335, Lys-372 and Lys-382 by SENP7 relieves inhibition and activates
CC CGAS (PubMed:28095500). {ECO:0000269|PubMed:27637147,
CC ECO:0000269|PubMed:28095500}.
CC -!- PTM: Polyglutamylated by TTLL6 at Glu-272, leading to impair DNA-
CC binding activity. Monoglutamylated at Glu-302 by TTLL4, leading to
CC impair the nucleotidyltransferase activity. Deglutamylated by
CC AGBL5/CCP5 and AGBL6/CCP6. {ECO:0000269|PubMed:26829768}.
CC -!- PTM: Acetylation at Lys-372, Lys-382 and Lys-402 inhibits the cyclic
CC GMP-AMP synthase activity. Deacetylated upon cytosolic DNA challenge
CC such as viral infections. Acetylation by KAT5 increases the cyclic GMP-
CC AMP synthase activity by promoting DNA-binding and subsequent
CC activation. {ECO:0000250|UniProtKB:Q8N884}.
CC -!- PTM: Proteolytically cleaved by apoptotic caspases during apoptosis,
CC leading to its inactivation (PubMed:25525874, PubMed:30878284). The
CC damage of the nucleus and the mitochondria during apoptosis leads to
CC leakage of nuclear and mitochondrial DNA, which activate CGAS: cleavage
CC and inactivation during apoptosis in required to prevent cytokine
CC overproduction (PubMed:25525874). Cleaved by CASP7 and CASP3 during
CC virus-induced apoptosis, thereby inactivating it and preventing
CC cytokine overproduction (PubMed:30878284). Cleaved by CASP1 upon DNA
CC virus infection; the cleavage impairs cGAMP production
CC (PubMed:28314590). Also cleaved by the pyroptotic CASP4 during non-
CC canonical inflammasome activation; does not cut at the same sites than
CC CASP1 (PubMed:28314590). {ECO:0000269|PubMed:25525874,
CC ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:30878284}.
CC -!- SIMILARITY: Belongs to the mab-21 family. {ECO:0000305}.
CC -!- CAUTION: Was reported to homodimerize in presence of double-stranded
CC DNA (dsDNA) (PubMed:24332030). However, this result was based on a
CC structure lacking the N-terminal part (1-146), which caused
CC homodimerization in presence of dsDNA (PubMed:28214358).
CC {ECO:0000269|PubMed:24332030}.
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DR EMBL; KC294567; AGB51854.1; -; mRNA.
DR EMBL; AK054330; BAC35733.1; -; mRNA.
DR EMBL; AK145268; BAE26335.1; -; mRNA.
DR EMBL; AC158987; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466522; EDL26396.1; -; Genomic_DNA.
DR EMBL; BC052196; AAH52196.1; -; mRNA.
DR EMBL; BC145651; AAI45652.1; -; mRNA.
DR EMBL; BC145653; AAI45654.1; -; mRNA.
DR CCDS; CCDS40702.1; -.
DR RefSeq; NP_775562.2; NM_173386.5.
DR PDB; 4K8V; X-ray; 2.00 A; A/B/C/D=147-507.
DR PDB; 4K96; X-ray; 2.08 A; A/B=147-507.
DR PDB; 4K97; X-ray; 2.41 A; A=147-507.
DR PDB; 4K98; X-ray; 1.94 A; A=147-507.
DR PDB; 4K99; X-ray; 1.95 A; A=147-507.
DR PDB; 4K9A; X-ray; 2.26 A; A=147-507.
DR PDB; 4K9B; X-ray; 2.26 A; A=147-507.
DR PDB; 4LEY; X-ray; 2.50 A; A/B/C/D=142-507.
DR PDB; 4LEZ; X-ray; 2.36 A; A/C=142-507.
DR PDB; 4O6A; X-ray; 1.86 A; A/B=147-507.
DR PDB; 5N6I; X-ray; 3.60 A; A/B/C/D/E/F=139-507.
DR PDB; 5XZB; X-ray; 2.13 A; A=149-505.
DR PDB; 5XZE; X-ray; 2.18 A; A=147-507.
DR PDB; 5XZG; X-ray; 1.83 A; A=147-507.
DR PDB; 6X59; EM; 2.98 A; K=142-507.
DR PDB; 6X5A; EM; 4.36 A; K=142-507.
DR PDB; 6XJD; EM; 6.80 A; K/L=142-507.
DR PDB; 7A08; EM; 3.11 A; a=139-507.
DR PDB; 7BUJ; X-ray; 2.13 A; A/B=61-507.
DR PDB; 7BUM; X-ray; 3.05 A; A/B=1-507.
DR PDB; 7BUQ; X-ray; 3.09 A; A/B=1-507.
DR PDB; 7JO9; EM; 3.30 A; K=142-507.
DR PDB; 7JOA; EM; 3.30 A; K=142-507.
DR PDB; 7KXS; X-ray; 2.60 A; A/B=147-507.
DR PDBsum; 4K8V; -.
DR PDBsum; 4K96; -.
DR PDBsum; 4K97; -.
DR PDBsum; 4K98; -.
DR PDBsum; 4K99; -.
DR PDBsum; 4K9A; -.
DR PDBsum; 4K9B; -.
DR PDBsum; 4LEY; -.
DR PDBsum; 4LEZ; -.
DR PDBsum; 4O6A; -.
DR PDBsum; 5N6I; -.
DR PDBsum; 5XZB; -.
DR PDBsum; 5XZE; -.
DR PDBsum; 5XZG; -.
DR PDBsum; 6X59; -.
DR PDBsum; 6X5A; -.
DR PDBsum; 6XJD; -.
DR PDBsum; 7A08; -.
DR PDBsum; 7BUJ; -.
DR PDBsum; 7BUM; -.
DR PDBsum; 7BUQ; -.
DR PDBsum; 7JO9; -.
DR PDBsum; 7JOA; -.
DR PDBsum; 7KXS; -.
DR AlphaFoldDB; Q8C6L5; -.
DR SMR; Q8C6L5; -.
DR STRING; 10090.ENSMUSP00000063331; -.
DR ChEMBL; CHEMBL4523383; -.
DR iPTMnet; Q8C6L5; -.
DR PhosphoSitePlus; Q8C6L5; -.
DR EPD; Q8C6L5; -.
DR MaxQB; Q8C6L5; -.
DR PaxDb; Q8C6L5; -.
DR PRIDE; Q8C6L5; -.
DR ProteomicsDB; 281655; -.
DR Antibodypedia; 31341; 221 antibodies from 32 providers.
DR DNASU; 214763; -.
DR Ensembl; ENSMUST00000070742; ENSMUSP00000063331; ENSMUSG00000032344.
DR GeneID; 214763; -.
DR KEGG; mmu:214763; -.
DR UCSC; uc009quj.2; mouse.
DR CTD; 115004; -.
DR MGI; MGI:2442261; Cgas.
DR VEuPathDB; HostDB:ENSMUSG00000032344; -.
DR eggNOG; KOG3963; Eukaryota.
DR GeneTree; ENSGT01050000244827; -.
DR HOGENOM; CLU_040428_2_0_1; -.
DR InParanoid; Q8C6L5; -.
DR OMA; CLRTEKL; -.
DR OrthoDB; 759341at2759; -.
DR PhylomeDB; Q8C6L5; -.
DR TreeFam; TF331255; -.
DR BRENDA; 2.7.7.86; 3474.
DR BioGRID-ORCS; 214763; 2 hits in 70 CRISPR screens.
DR ChiTaRS; Cgas; mouse.
DR PRO; PR:Q8C6L5; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q8C6L5; protein.
DR Bgee; ENSMUSG00000032344; Expressed in secondary oocyte and 116 other tissues.
DR ExpressionAtlas; Q8C6L5; baseline and differential.
DR Genevisible; Q8C6L5; MM.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0035861; C:site of double-strand break; ISS:UniProtKB.
DR GO; GO:0061501; F:2',3'-cyclic GMP-AMP synthase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031491; F:nucleosome binding; IDA:UniProtKB.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0002218; P:activation of innate immune response; IDA:UniProtKB.
DR GO; GO:0019933; P:cAMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0071360; P:cellular response to exogenous dsRNA; IDA:UniProtKB.
DR GO; GO:0019934; P:cGMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; IGI:MGI.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:2000042; P:negative regulation of double-strand break repair via homologous recombination; IDA:UniProtKB.
DR GO; GO:0038001; P:paracrine signaling; IDA:UniProtKB.
DR GO; GO:2000774; P:positive regulation of cellular senescence; IDA:UniProtKB.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IDA:UniProtKB.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProtKB.
DR GO; GO:0050776; P:regulation of immune response; IGI:MGI.
DR GO; GO:0002637; P:regulation of immunoglobulin production; IGI:MGI.
DR GO; GO:0050863; P:regulation of T cell activation; IGI:MGI.
DR GO; GO:0032479; P:regulation of type I interferon production; IGI:MGI.
DR InterPro; IPR024810; Mab-21_dom.
DR Pfam; PF03281; Mab-21; 1.
DR SMART; SM01265; Mab-21; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Antiviral defense; ATP-binding; Cell membrane;
KW Chromosome; Cytoplasm; DNA damage; DNA repair; DNA-binding; GTP-binding;
KW Immunity; Innate immunity; Isopeptide bond; Lipid-binding; Magnesium;
KW Membrane; Metal-binding; Nucleotide-binding; Nucleotidyltransferase;
KW Nucleus; Phosphoprotein; Reference proteome; Transferase; Ubl conjugation;
KW Zinc.
FT CHAIN 1..507
FT /note="Cyclic GMP-AMP synthase"
FT /id="PRO_0000421764"
FT REGION 1..151
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1..146
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:28363908"
FT REGION 48..59
FT /note="Required for association with the cell membrane"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT REGION 119..132
FT /note="Required for activation upon DNA viral infection"
FT /evidence="ECO:0000269|PubMed:28314590"
FT REGION 158..201
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:23647843,
FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528,
FT ECO:0007744|PDB:5N6I"
FT REGION 329..370
FT /note="Interaction with collided ribosomes"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT REGION 372..395
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:23647843,
FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528,
FT ECO:0007744|PDB:5N6I"
FT MOTIF 154..159
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT MOTIF 281..291
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT COMPBIAS 38..61
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 197
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 199
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 211
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 213
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24332030,
FT ECO:0007744|PDB:4LEZ"
FT BINDING 213
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 290
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24332030,
FT ECO:0007744|PDB:4LEZ"
FT BINDING 307
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24332030,
FT ECO:0007744|PDB:4LEZ"
FT BINDING 307
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 307
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 350
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24332030,
FT ECO:0007744|PDB:4LEZ"
FT BINDING 364..371
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 364..366
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24332030,
FT ECO:0007744|PDB:4LEZ"
FT BINDING 371
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 378
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23647843,
FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528,
FT ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:32913000, ECO:0007744|PDB:5N6I,
FT ECO:0007744|PDB:5XZB, ECO:0007744|PDB:5XZE,
FT ECO:0007744|PDB:5XZG, ECO:0007744|PDB:6X59,
FT ECO:0007744|PDB:7BUJ, ECO:0007744|PDB:7BUM,
FT ECO:0007744|PDB:7BUQ, ECO:0007744|PDB:7JO9,
FT ECO:0007744|PDB:7JOA"
FT BINDING 384
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23647843,
FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528,
FT ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:32913000, ECO:0007744|PDB:5N6I,
FT ECO:0007744|PDB:5XZB, ECO:0007744|PDB:5XZE,
FT ECO:0007744|PDB:5XZG, ECO:0007744|PDB:6X59,
FT ECO:0007744|PDB:7BUJ, ECO:0007744|PDB:7BUM,
FT ECO:0007744|PDB:7BUQ, ECO:0007744|PDB:7JO9,
FT ECO:0007744|PDB:7JOA"
FT BINDING 385
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23647843,
FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528,
FT ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:32913000, ECO:0007744|PDB:5N6I,
FT ECO:0007744|PDB:5XZB, ECO:0007744|PDB:5XZE,
FT ECO:0007744|PDB:5XZG, ECO:0007744|PDB:6XJD,
FT ECO:0007744|PDB:7BUJ, ECO:0007744|PDB:7BUM,
FT ECO:0007744|PDB:7BUQ, ECO:0007744|PDB:7JO9,
FT ECO:0007744|PDB:7JOA"
FT BINDING 392
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23647843,
FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:28902841, ECO:0000269|PubMed:28963528,
FT ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32911480,
FT ECO:0000269|PubMed:32911481, ECO:0000269|PubMed:32913000,
FT ECO:0007744|PDB:5N6I, ECO:0007744|PDB:5XZB,
FT ECO:0007744|PDB:5XZE, ECO:0007744|PDB:5XZG,
FT ECO:0007744|PDB:6X5A, ECO:0007744|PDB:7BUJ,
FT ECO:0007744|PDB:7BUM, ECO:0007744|PDB:7BUQ,
FT ECO:0007744|PDB:7JO9, ECO:0007744|PDB:7JOA"
FT BINDING 402
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23647843"
FT BINDING 420..424
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:23647843"
FT SITE 241
FT /note="Arginine-anchor"
FT /evidence="ECO:0000269|PubMed:31808743,
FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:32913000"
FT SITE 307..308
FT /note="Cleavage; by CASP3"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT MOD_RES 52
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT MOD_RES 199
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT MOD_RES 201
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT MOD_RES 272
FT /note="5-glutamyl polyglutamate"
FT /evidence="ECO:0000269|PubMed:26829768"
FT MOD_RES 291
FT /note="Phosphoserine; by CDK1 and PKB"
FT /evidence="ECO:0000269|PubMed:26440888,
FT ECO:0000269|PubMed:32351706"
FT MOD_RES 302
FT /note="5-glutamyl glutamate"
FT /evidence="ECO:0000269|PubMed:26829768"
FT MOD_RES 372
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT MOD_RES 382
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT MOD_RES 402
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT MOD_RES 420
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:32474700"
FT CROSSLNK 217
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000269|PubMed:27637147"
FT CROSSLNK 271
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:27637147,
FT ECO:0000269|PubMed:32457395"
FT CROSSLNK 335
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000269|PubMed:28095500"
FT CROSSLNK 335
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000269|PubMed:29426904"
FT CROSSLNK 372
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000269|PubMed:28095500"
FT CROSSLNK 372
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT CROSSLNK 382
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000269|PubMed:28095500"
FT CROSSLNK 402
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q8N884"
FT CROSSLNK 464
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000269|PubMed:27637147"
FT CROSSLNK 464
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000269|PubMed:27637147,
FT ECO:0000269|PubMed:32457395"
FT MUTAGEN 172
FT /note="N->K: Induces alteration of the DNA-binding surface
FT and leads to decreased synthesis of cyclic GMP-AMP (cGAMP);
FT when associated with L-180."
FT /evidence="ECO:0000269|PubMed:30007416"
FT MUTAGEN 180
FT /note="R->L: Induces alteration of the DNA-binding surface
FT and leads to decreased synthesis of cyclic GMP-AMP (cGAMP);
FT when associated with K-182."
FT /evidence="ECO:0000269|PubMed:30007416"
FT MUTAGEN 198
FT /note="G->A: Abolishes stimulation of interferon
FT production; when associated with A-199."
FT /evidence="ECO:0000269|PubMed:26229117"
FT MUTAGEN 199
FT /note="S->A: Abolishes stimulation of interferon
FT production; when associated with A-199."
FT /evidence="ECO:0000269|PubMed:26229117"
FT MUTAGEN 211..213
FT /note="EFD->AFA: Abolished nucleotidyltransferase activity.
FT Does not affect nuclear localization and tethering to
FT chromatin."
FT /evidence="ECO:0000269|PubMed:31808743"
FT MUTAGEN 211
FT /note="E->A: Abolishes ability to promote type-I interferon
FT production."
FT /evidence="ECO:0000269|PubMed:23258413"
FT MUTAGEN 213
FT /note="D->A: Abolishes ability to promote type-I interferon
FT production."
FT /evidence="ECO:0000269|PubMed:23258413"
FT MUTAGEN 217
FT /note="K->R: Reduced sumoylation."
FT /evidence="ECO:0000269|PubMed:27637147"
FT MUTAGEN 222
FT /note="R->E: Impaired tethering to chromatin, leading to
FT constitutive activation in the absence of DNA."
FT /evidence="ECO:0000269|PubMed:31808743,
FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:32913000"
FT MUTAGEN 238
FT /note="K->E: Does not affect interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481"
FT MUTAGEN 240
FT /note="K->E: Impaired tethering to chromatin, leading to
FT constitutive activation in the absence of DNA."
FT /evidence="ECO:0000269|PubMed:31808743,
FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:32913000"
FT MUTAGEN 241
FT /note="R->E: Abolished tethering to chromatin, leading to
FT strong constitutive activation in the absence of DNA."
FT /evidence="ECO:0000269|PubMed:31808743,
FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:32913000"
FT MUTAGEN 242..247
FT /note="IPRGNP->SGSGSG: Slightly decreased tethering to
FT chromatin, leading to mild constitutive activation in the
FT absence of DNA."
FT /evidence="ECO:0000269|PubMed:31808743"
FT MUTAGEN 244
FT /note="R->E: Slightly decreased tethering to chromatin.
FT Does not affect interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:31808743,
FT ECO:0000269|PubMed:32911481"
FT MUTAGEN 271
FT /note="K->R: Impaired deubiquitination by USP29. Does not
FT affect sumoylation."
FT /evidence="ECO:0000269|PubMed:27637147,
FT ECO:0000269|PubMed:32457395"
FT MUTAGEN 272
FT /note="E->A: Increased DNA-binding activity."
FT /evidence="ECO:0000269|PubMed:26829768"
FT MUTAGEN 278
FT /note="K->R: Does not affect ubiquitination by TRIM56."
FT /evidence="ECO:0000269|PubMed:29426904"
FT MUTAGEN 291
FT /note="S->A: Enhanced stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:26440888"
FT MUTAGEN 302
FT /note="E->A: Increased nucleotidyltransferase activity."
FT /evidence="ECO:0000269|PubMed:26829768"
FT MUTAGEN 315
FT /note="K->E: Slightly decreased interaction with
FT nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481"
FT MUTAGEN 323
FT /note="K->E: Slightly decreased interaction with
FT nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481"
FT MUTAGEN 335
FT /note="K->E: Decreased DNA-binding and subsequent
FT activation. Does not affect nuclear localization and
FT tethering to chromatin."
FT /evidence="ECO:0000269|PubMed:31808743,
FT ECO:0000269|PubMed:32911481"
FT MUTAGEN 335
FT /note="K->R: Abolished ubiquitination by TRIM56, leading to
FT impaired homodimerization and activation. Does not affect
FT sumoylation. Strongly reduced sumoylation; when associated
FT with R-372 and R-382."
FT /evidence="ECO:0000269|PubMed:27637147,
FT ECO:0000269|PubMed:28095500, ECO:0000269|PubMed:29426904"
FT MUTAGEN 337
FT /note="R->E: Strongly reduced interaction with
FT nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911480"
FT MUTAGEN 341
FT /note="R->E: Abolished interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911480,
FT ECO:0000269|PubMed:32911481"
FT MUTAGEN 342
FT /note="R->E: Strongly decreased interaction with
FT nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911480,
FT ECO:0000269|PubMed:32911481"
FT MUTAGEN 350
FT /note="K->R: Does not affect ubiquitination by TRIM56."
FT /evidence="ECO:0000269|PubMed:29426904"
FT MUTAGEN 372
FT /note="K->R: Strongly reduced sumoylation; when associated
FT with R-335 and R-382."
FT /evidence="ECO:0000269|PubMed:28095500"
FT MUTAGEN 382
FT /note="K->A: Decreased DNA-binding and abolished
FT homodimerization. Does not affect nuclear localization and
FT tethering to chromatin."
FT /evidence="ECO:0000269|PubMed:31808743"
FT MUTAGEN 382
FT /note="K->E: Slightly decreased interaction with
FT nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481"
FT MUTAGEN 382
FT /note="K->R: Strongly reduced sumoylation; when associated
FT with R-335 and R-372."
FT /evidence="ECO:0000269|PubMed:28095500"
FT MUTAGEN 386
FT /note="E->A: Abolished homodimerization and subsequent
FT activation. Does not affect nuclear localization and
FT tethering to chromatin."
FT /evidence="ECO:0000269|PubMed:31808743"
FT MUTAGEN 395..399
FT /note="KECLK->MECLM: Decreased DNA-binding and subsequent
FT activation. Does not affect nuclear localization and
FT tethering to chromatin."
FT /evidence="ECO:0000269|PubMed:31808743"
FT MUTAGEN 419
FT /note="C->S: Gains susceptibility to mouse-specific RU.521;
FT when associated with N-467."
FT /evidence="ECO:0000269|PubMed:30007416"
FT MUTAGEN 420
FT /note="S->A: Decreased cyclic GMP-AMP synthase activity."
FT /evidence="ECO:0000269|PubMed:32474700"
FT MUTAGEN 420
FT /note="S->D: Phospho-mimetic mutant; increased cyclic GMP-
FT AMP synthase activity."
FT /evidence="ECO:0000269|PubMed:32474700"
FT MUTAGEN 464
FT /note="K->R: Does not affect deubiquitination by USP29.
FT Reduced sumoylation."
FT /evidence="ECO:0000269|PubMed:27637147,
FT ECO:0000269|PubMed:32457395"
FT MUTAGEN 467
FT /note="H->N: Gains susceptibility to mouse-specific RU.521;
FT when associated with S-419."
FT /evidence="ECO:0000269|PubMed:30007416"
FT CONFLICT 6
FT /note="R -> I (in Ref. 2; BAE26335)"
FT /evidence="ECO:0000305"
FT CONFLICT 471
FT /note="P -> R (in Ref. 2; BAE26335)"
FT /evidence="ECO:0000305"
FT HELIX 150..157
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 161..183
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 184..186
FT /evidence="ECO:0007829|PDB:5XZG"
FT TURN 188..191
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 193..198
FT /evidence="ECO:0007829|PDB:5XZG"
FT TURN 199..203
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 207..209
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 211..219
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 222..227
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 229..231
FT /evidence="ECO:0007829|PDB:7JO9"
FT STRAND 232..241
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 247..251
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 252..257
FT /evidence="ECO:0007829|PDB:4O6A"
FT HELIX 259..275
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 279..284
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 293..314
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 320..322
FT /evidence="ECO:0007829|PDB:5XZG"
FT TURN 329..332
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 334..341
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 345..348
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 352..354
FT /evidence="ECO:0007829|PDB:4K98"
FT STRAND 355..358
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 359..361
FT /evidence="ECO:0007829|PDB:4O6A"
FT STRAND 363..366
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 368..376
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 379..381
FT /evidence="ECO:0007829|PDB:7BUJ"
FT TURN 382..385
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 386..389
FT /evidence="ECO:0007829|PDB:6X59"
FT HELIX 394..411
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 413..415
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 420..433
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 437..440
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 442..444
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 445..462
FT /evidence="ECO:0007829|PDB:5XZG"
FT STRAND 468..470
FT /evidence="ECO:0007829|PDB:4O6A"
FT STRAND 474..476
FT /evidence="ECO:0007829|PDB:7A08"
FT TURN 478..480
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 483..498
FT /evidence="ECO:0007829|PDB:5XZG"
FT HELIX 502..504
FT /evidence="ECO:0007829|PDB:5XZG"
SQ SEQUENCE 507 AA; 58194 MW; 9FDA84DF5E4859CA CRC64;
MEDPRRRTTA PRAKKPSAKR APTQPSRTRA HAESCGPQRG ARSRRAERDG DTTEKPRAPG
PRVHPARATE LTKDAQPSAM DAAGATARPA VRVPQQQAIL DPELPAVREP QPPADPEARK
VVRGPSHRRG ARSTGQPRAP RGSRKEPDKL KKVLDKLRLK RKDISEAAET VNKVVERLLR
RMQKRESEFK GVEQLNTGSY YEHVKISAPN EFDVMFKLEV PRIELQEYYE TGAFYLVKFK
RIPRGNPLSH FLEGEVLSAT KMLSKFRKII KEEVKEIKDI DVSVEKEKPG SPAVTLLIRN
PEEISVDIIL ALESKGSWPI STKEGLPIQG WLGTKVRTNL RREPFYLVPK NAKDGNSFQG
ETWRLSFSHT EKYILNNHGI EKTCCESSGA KCCRKECLKL MKYLLEQLKK EFQELDAFCS
YHVKTAIFHM WTQDPQDSQW DPRNLSSCFD KLLAFFLECL RTEKLDHYFI PKFNLFSQEL
IDRKSKEFLS KKIEYERNNG FPIFDKL
