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Protein

Cyclic GMP-AMP synthase

Gene

Cgas

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (cGAMP) from ATP and GTP (PubMed:23258413, PubMed:23647843, PubMed:23722158, PubMed:26829768, PubMed:28214358). Catalysis involves both the formation of a 2',5' phosphodiester linkage at the GpA step and the formation of a 3',5' phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p] (PubMed:23258413, PubMed:23647843, PubMed:23722158, PubMed:26829768, PubMed:28214358). Acts as a key cytosolic DNA sensor, the presence of double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that triggers the immune responses (PubMed:23722158, PubMed:28363908, PubMed:28314590). Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production (PubMed:23722158, PubMed:28363908, PubMed:28314590). Has antiviral activity by sensing the presence of dsDNA from DNA viruses in the cytoplasm (PubMed:23258413, PubMed:23647843, PubMed:23722158). Also acts as an innate immune sensor of infection by retroviruses by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:23929945). Detection of retroviral reverse-transcribed DNA in the cytosol may be indirect and be mediated via interaction with PQBP1, which directly binds reverse-transcribed retroviral DNA (By similarity). Also detects the presence of DNA from bacteria (By similarity). cGAMP can be transferred from producing cells to neighboring cells through gap junctions, leading to promote TMEM173/STING activation and convey immune response to connecting cells (PubMed:24077100). cGAMP can also be transferred between cells by virtue of packaging within viral particles contributing to IFN-induction in newly infected cells in a cGAS-independent but TMEM173/STING-dependent manner (PubMed:26229117). In addition to antiviral activity, also involved in the response to cellular stresses, such as senescence, DNA damage or genome instability (PubMed:28738408, PubMed:28759028). Acts as a regulator of cellular senescence by binding to cytosolic chromatin fragments that are present in senescent cells, leading to trigger type-I interferon production via TMEM173/STING and promote cellular senescence (PubMed:28759028). Also involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability (PubMed:28738408). Micronuclei, which as frequently found in cancer cells, consist of chromatin surrounded by its own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, CGAS binds self-DNA exposed to the cytosol, leading to cGAMP synthesis and subsequent activation of TMEM173/STING and type-I interferon production (PubMed:28738408).By similarity12 Publications

Caution

Was reported to homodimerize in presence of double-stranded DNA (dsDNA) (PubMed:24332030). However, this result was based on a structure lacking the N-terminal part (1-146), which caused homodimerization in presence of dsDNA (PubMed:28214358).1 Publication

Catalytic activityi

ATP + GTP = 2 diphosphate + cyclic G-P(2'-5')A-P(3'-5').1 Publication

Cofactori

Mg2+1 Publication, Mn2+1 PublicationNote: Binds 1 Mg2+ per subunit. Is also active with Mn2+.1 Publication

Activity regulationi

Nucleotidyltransferase activity is stimulated by double-stranded DNA but not RNA (By similarity). The enzyme activity is impaired by the cleavage by CASP1 (PubMed:28314590).By similarity1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei197GTP1 Publication1
Binding sitei199ATP1 Publication1
Metal bindingi211Magnesium; catalytic1 Publication1
Metal bindingi213Magnesium; catalytic1 Publication1
Metal bindingi307Magnesium; catalytic1 Publication1
Binding sitei307GTP1 Publication1
Binding sitei371ATP1 Publication1
Metal bindingi378Zinc; via tele nitrogen3 Publications1
Metal bindingi384Zinc3 Publications1
Metal bindingi385Zinc3 Publications1
Metal bindingi392Zinc3 Publications1
Binding sitei402ATP1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi364 – 371GTP1 Publication8
Nucleotide bindingi420 – 424ATP1 Publication5

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionDNA-binding, Nucleotidyltransferase, Transferase
Biological processAntiviral defense, Immunity, Innate immunity
LigandATP-binding, GTP-binding, Magnesium, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BRENDAi2.7.7.86 3474

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclic GMP-AMP synthase1 Publication (EC:2.7.7.861 Publication)
Short name:
cGAMP synthase1 Publication
Short name:
cGAS1 Publication
Short name:
m-cGAS1 Publication
Alternative name(s):
2'3'-cGAMP synthase1 Publication
Mab-21 domain-containing protein 1
Gene namesi
Name:CgasBy similarity
Synonyms:Mb21d1Imported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:2442261 Cgas

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi198G → A: Abolishes stimulation of interferon production; when associated with A-199. 1 Publication1
Mutagenesisi199S → A: Abolishes stimulation of interferon production; when associated with A-199. 1 Publication1
Mutagenesisi211E → A: Abolishes ability to promote type-I interferon production. 1 Publication1
Mutagenesisi213D → A: Abolishes ability to promote type-I interferon production. 1 Publication1
Mutagenesisi272E → A: Increased DNA-binding activity. 1 Publication1
Mutagenesisi302E → A: Increased nucleotidyltransferase activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00004217641 – 507Cyclic GMP-AMP synthaseAdd BLAST507

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2725-glutamyl polyglutamate1 Publication1
Modified residuei3025-glutamyl glutamate1 Publication1
Modified residuei402N6-acetyllysineBy similarity1

Post-translational modificationi

Polyglutamylated by TTLL6 at Glu-272, leading to impair DNA-binding activity. Monoglutamylated at Glu-302 by TTLL4, leading to impair the nucleotidyltransferase activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6.1 Publication
Cleaved by CASP1 upon DNA virus infection; the cleavage impairs cGAMP production (PubMed:28314590). Also cleaved by the pyroptotic CASP4 during non-canonical inflammasome activation; does not cut at the same sites than CASP1 (PubMed:28314590).1 Publication

Keywords - PTMi

Acetylation, Isopeptide bond

Proteomic databases

EPDiQ8C6L5
MaxQBiQ8C6L5
PaxDbiQ8C6L5
PRIDEiQ8C6L5

PTM databases

iPTMnetiQ8C6L5
PhosphoSitePlusiQ8C6L5

Expressioni

Gene expression databases

BgeeiENSMUSG00000032344 Expressed in 120 organ(s), highest expression level in embryo
ExpressionAtlasiQ8C6L5 baseline and differential
GenevisibleiQ8C6L5 MM

Interactioni

Subunit structurei

Monomer in the absence of DNA and when bound to dsDNA (PubMed:28214358). Interacts with PQBP1 (via WW domain). Interacts with TRIM14; this interaction stabilizes CGAS and promotes type I interferon production.By similarity1 Publication

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000063331

Structurei

Secondary structure

1507
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ8C6L5
SMRiQ8C6L5
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 146DNA-binding1 PublicationAdd BLAST146
Regioni119 – 132Required for activation upon DNA viral infection1 PublicationAdd BLAST14
Regioni158 – 201DNA-binding1 PublicationAdd BLAST44
Regioni372 – 395DNA-binding1 PublicationAdd BLAST24

Domaini

The N-terminal part (1-146) binds unspecifically dsDNA and expand the binding and moving range of CGAS on dsDNA. Enhances the enzyme activity and activation of innate immune signaling upon cytosolic recognition of dsDNA (PubMed:28363908, PubMed:28214358, PubMed:28314590). When the N-terminal part (1-146) is missing the protein bound to dsDNA homodimerizes (PubMed:28214358).3 Publications

Sequence similaritiesi

Belongs to the mab-21 family.Curated

Phylogenomic databases

eggNOGiENOG410IE27 Eukaryota
ENOG410XTKD LUCA
GeneTreeiENSGT00710000106842
HOGENOMiHOG000293423
HOVERGENiHBG068840
InParanoidiQ8C6L5
KOiK17834
OMAiPQDSQWD
OrthoDBiEOG091G0MHW
TreeFamiTF331255

Family and domain databases

InterProiView protein in InterPro
IPR024810 Mab-21_dom
PfamiView protein in Pfam
PF03281 Mab-21, 1 hit
SMARTiView protein in SMART
SM01265 Mab-21, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

Q8C6L5-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MEDPRRRTTA PRAKKPSAKR APTQPSRTRA HAESCGPQRG ARSRRAERDG
60 70 80 90 100
DTTEKPRAPG PRVHPARATE LTKDAQPSAM DAAGATARPA VRVPQQQAIL
110 120 130 140 150
DPELPAVREP QPPADPEARK VVRGPSHRRG ARSTGQPRAP RGSRKEPDKL
160 170 180 190 200
KKVLDKLRLK RKDISEAAET VNKVVERLLR RMQKRESEFK GVEQLNTGSY
210 220 230 240 250
YEHVKISAPN EFDVMFKLEV PRIELQEYYE TGAFYLVKFK RIPRGNPLSH
260 270 280 290 300
FLEGEVLSAT KMLSKFRKII KEEVKEIKDI DVSVEKEKPG SPAVTLLIRN
310 320 330 340 350
PEEISVDIIL ALESKGSWPI STKEGLPIQG WLGTKVRTNL RREPFYLVPK
360 370 380 390 400
NAKDGNSFQG ETWRLSFSHT EKYILNNHGI EKTCCESSGA KCCRKECLKL
410 420 430 440 450
MKYLLEQLKK EFQELDAFCS YHVKTAIFHM WTQDPQDSQW DPRNLSSCFD
460 470 480 490 500
KLLAFFLECL RTEKLDHYFI PKFNLFSQEL IDRKSKEFLS KKIEYERNNG

FPIFDKL
Length:507
Mass (Da):58,194
Last modified:March 1, 2003 - v1
Checksum:i9FDA84DF5E4859CA
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
F6ZBV6F6ZBV6_MOUSE
Cyclic GMP-AMP synthase
Cgas E330016A19Rik
230Annotation score:
D3Z5R0D3Z5R0_MOUSE
Cyclic GMP-AMP synthase
Cgas E330016A19Rik, mCG_15229
394Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti6R → I in BAE26335 (PubMed:16141072).Curated1
Sequence conflicti471P → R in BAE26335 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
KC294567 mRNA Translation: AGB51854.1
AK054330 mRNA Translation: BAC35733.1
AK145268 mRNA Translation: BAE26335.1
AC158987 Genomic DNA No translation available.
CH466522 Genomic DNA Translation: EDL26396.1
BC052196 mRNA Translation: AAH52196.1
BC145651 mRNA Translation: AAI45652.1
BC145653 mRNA Translation: AAI45654.1
CCDSiCCDS40702.1
RefSeqiNP_775562.2, NM_173386.5
UniGeneiMm.101559

Genome annotation databases

EnsembliENSMUST00000070742; ENSMUSP00000063331; ENSMUSG00000032344
GeneIDi214763
KEGGimmu:214763
UCSCiuc009quj.2 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
KC294567 mRNA Translation: AGB51854.1
AK054330 mRNA Translation: BAC35733.1
AK145268 mRNA Translation: BAE26335.1
AC158987 Genomic DNA No translation available.
CH466522 Genomic DNA Translation: EDL26396.1
BC052196 mRNA Translation: AAH52196.1
BC145651 mRNA Translation: AAI45652.1
BC145653 mRNA Translation: AAI45654.1
CCDSiCCDS40702.1
RefSeqiNP_775562.2, NM_173386.5
UniGeneiMm.101559

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4K8VX-ray2.00A/B/C/D147-507[»]
4K96X-ray2.08A/B147-507[»]
4K97X-ray2.41A147-507[»]
4K98X-ray1.94A147-507[»]
4K99X-ray1.95A147-507[»]
4K9AX-ray2.26A147-507[»]
4K9BX-ray2.26A147-507[»]
4LEYX-ray2.50A/B/C/D142-507[»]
4LEZX-ray2.36A/C142-507[»]
4O6AX-ray1.86A/B147-507[»]
5N6IX-ray3.60A/B/C/D/E/F139-507[»]
5XZBX-ray2.13A149-505[»]
5XZEX-ray2.18A147-507[»]
5XZGX-ray1.83A147-507[»]
ProteinModelPortaliQ8C6L5
SMRiQ8C6L5
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000063331

PTM databases

iPTMnetiQ8C6L5
PhosphoSitePlusiQ8C6L5

Proteomic databases

EPDiQ8C6L5
MaxQBiQ8C6L5
PaxDbiQ8C6L5
PRIDEiQ8C6L5

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000070742; ENSMUSP00000063331; ENSMUSG00000032344
GeneIDi214763
KEGGimmu:214763
UCSCiuc009quj.2 mouse

Organism-specific databases

CTDi115004
MGIiMGI:2442261 Cgas

Phylogenomic databases

eggNOGiENOG410IE27 Eukaryota
ENOG410XTKD LUCA
GeneTreeiENSGT00710000106842
HOGENOMiHOG000293423
HOVERGENiHBG068840
InParanoidiQ8C6L5
KOiK17834
OMAiPQDSQWD
OrthoDBiEOG091G0MHW
TreeFamiTF331255

Enzyme and pathway databases

BRENDAi2.7.7.86 3474

Miscellaneous databases

PROiPR:Q8C6L5
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000032344 Expressed in 120 organ(s), highest expression level in embryo
ExpressionAtlasiQ8C6L5 baseline and differential
GenevisibleiQ8C6L5 MM

Family and domain databases

InterProiView protein in InterPro
IPR024810 Mab-21_dom
PfamiView protein in Pfam
PF03281 Mab-21, 1 hit
SMARTiView protein in SMART
SM01265 Mab-21, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCGAS_MOUSE
AccessioniPrimary (citable) accession number: Q8C6L5
Secondary accession number(s): Q3ULW3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 6, 2013
Last sequence update: March 1, 2003
Last modified: November 7, 2018
This is version 111 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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Main funding by: National Institutes of Health

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