Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Cyclic GMP-AMP synthase

Gene

MB21D1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (cGAMP) from ATP and GTP (PubMed:28314590). 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:28363908, PubMed:28214358). Has antiviral activity by acting 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:28363908). 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:28363908, PubMed:28314590). cGAMP can 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:26229115).13 Publications
(Microbial infection) Upon M.tuberculosis infection THP-1 cells knocked-out for this gene have impaired type-I interferon production (IF-1 beta), nor do they produce type-I IFN upon transfection with dsDNA (PubMed:26048138).1 Publication

Catalytic activityi

ATP + GTP = 2 diphosphate + cyclic G-P(2'-5')A-P(3'-5').4 Publications

Cofactori

Mg2+By similarityNote: Binds 1 Mg2+ ion per subunit.By similarity

Enzyme regulationi

The enzyme activity is strongly increased by double-stranded DNA, but not by single-stranded DNA or RNA (PubMed:23258413, PubMed:23707061, PubMed:26300263). The enzyme activity is impaired by the cleavage at Asp-140 and Asp-157 produced by CASP1 (PubMed:28314590).4 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei211GTPBy similarity1
Binding sitei213ATPBy similarity1
Metal bindingi225Magnesium; catalyticCurated1
Metal bindingi227Magnesium; catalyticCurated1
Metal bindingi319Magnesium; catalyticBy similarity1
Binding sitei319GTP1 Publication1
Binding sitei383ATPBy similarity1
Metal bindingi390Zinc; via tele nitrogen3 Publications1
Metal bindingi396Zinc3 Publications1
Metal bindingi397Zinc3 Publications1
Metal bindingi404Zinc3 Publications1
Binding sitei414ATPBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi376 – 383GTP1 Publication8
Nucleotide bindingi435 – 439ATP1 Publication5

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • cyclic-GMP-AMP synthase activity Source: UniProtKB
  • DNA binding Source: UniProtKB
  • double-stranded DNA binding Source: UniProtKB
  • GTP binding Source: UniProtKB-KW
  • metal ion binding Source: UniProtKB-KW

GO - Biological processi

  • activation of innate immune response Source: UniProtKB
  • cellular response to exogenous dsRNA Source: UniProtKB
  • cyclic nucleotide biosynthetic process Source: UniProtKB
  • defense response to virus Source: UniProtKB
  • innate immune response Source: UniProtKB-KW
  • positive regulation of defense response to virus by host Source: UniProtKB
  • positive regulation of type I interferon production Source: UniProtKB

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. 2681.
ReactomeiR-HSA-1834941. STING mediated induction of host immune responses.

Names & Taxonomyi

Protein namesi
Recommended name:
Cyclic GMP-AMP synthase (EC:2.7.7.864 Publications)
Short name:
cGAMP synthase
Short name:
cGAS
Short name:
h-cGAS
Alternative name(s):
2'3'-cGAMP synthase
Mab-21 domain-containing protein 1
Gene namesi
Name:MB21D1
Synonyms:C6orf150
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:21367. MB21D1.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: UniProtKB

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi33D → A: No effect on type I IFN and RSAD2 induction. No effect on cleavage by CASP1. No effect on cleavage by CASP1; when associated with A-67; A-90 and A-95. Highly decreases cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-67; A-90; A-95 and A-140. Abolishes cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-67; A-90; A-95; A-140 and A-157. 1 Publication1
Mutagenesisi67D → A: No effect on type I IFN and RSAD2 induction. No effect on cleavage by CASP1; when associated with A-33; A-90 and A-95. Highly decreases cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when assocaited with A-33; A-90; A-95 and A-140. Abolishes cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-33; A-90; A-95; A-140 and A-157. 1 Publication1
Mutagenesisi90D → A: No effect on type I IFN and RSAD2 induction. No effect on cleavage by CASP1; when associated with A-33; A-67 and A-95. Highly decreases cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-33; A-67; A-95 and A-140. Abolishes cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-33; A-67; A-95; A-140 and A-157. 1 Publication1
Mutagenesisi95D → A: No effect on type I IFN and RSAD2 induction. No effect on cleavage by CASP1; when associated with A-33; A-67 and A-90. Highly decreases cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-33; A-67; A-90 and A-140. Abolishes cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-33; A-67; A-90; A-140 and A-157. 1 Publication1
Mutagenesisi140D → A: Highly decreases cleavage by CASP1 and enhances type I IFN and RSAD2 induction upon DNA virus infection. Abolishes cleavage by CASP1, enhances RSAD2 induction upon DNA virus infection but no effect on cleavage by CASP5; when associated with A-157. Highly decreases cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-33; A-67; A-90 and A-95. Abolishes cleavage by CASP1 and enhances RSAD2 induction upon DNA virus infection; when associated with A-33; A-67; A-90; A-95 and A-157. 1 Publication1
Mutagenesisi140D → H: Highly decreases cleavage by CASP1 and enhances type I IFN and RSAD2 induction upon DNA virus infection. 1 Publication1
Mutagenesisi157D → A: No effect on type I IFN and RSAD2 induction. Highly decreases cleavage by CASP1 and enhances type I IFN and enhances RSAD2 induction upon DNA virus infection. Abolishes cleavage by CASP1, enhances RSAD2 induction upon DNA virus infection but no effect on cleavage by CASP5; when associated with A-140. Abolishes cleavage by CASP1; when associated with A-33; A-67; A-90; A-95 and A-140. 1 Publication1
Mutagenesisi157D → H: Highly decreases cleavage by CASP1 and enhances type I IFN and enhances RSAD2 induction upon DNA virus infection. 1 Publication1
Mutagenesisi171K → A: No effect on stimulation of interferon production. 1 Publication1
Mutagenesisi173K → A: Strongly reduces enzyme activity and stimulation of interferon production; when associated with A-176. No effect on stimulation of interferon production. 3 Publications1
Mutagenesisi173K → E: Strongly reduces stimulation of interferon production. 2 Publications1
Mutagenesisi174L → N: Strongly reduces enzyme activity and stimulation of interferon production. 2 Publications1
Mutagenesisi176R → A: Strongly reduces enzyme activity and stimulation of interferon production; when associated with A-173. 1 Publication1
Mutagenesisi211T → Q: Abolishes enzyme activity; when associated with I-376 and I-436. 1 Publication1
Mutagenesisi212 – 213GS → AA: Abolishes enzyme activity. Abolishes stimulation of interferon production. 1 Publication2
Mutagenesisi225E → A: Abolishes enzyme activity and stimulation of interferon production; when associated with A-227. 3 Publications1
Mutagenesisi227D → A: Abolishes enzyme activity and stimulation of interferon production; when associated with A-225. 3 Publications1
Mutagenesisi236R → E: Abolishes stimulation of interferon production; when associated with E-254 and E-327. 1 Publication1
Mutagenesisi254K → E: Abolishes stimulation of interferon production; when associated with E-236 and E-327. 1 Publication1
Mutagenesisi327K → E: Abolishes stimulation of interferon production; when associated with E-236 and E-254. 1 Publication1
Mutagenesisi347K → E: Abolishes stimulation of interferon production. 1 Publication1
Mutagenesisi353R → E: Abolishes stimulation of interferon production. 1 Publication1
Mutagenesisi376R → I: Alters enzyme activity, leading to the appearance of 3'-5' linked cGAMP. Abolishes enzyme activity; when associated with Q-211 and I-436. 1 Publication1
Mutagenesisi384K → A or E: Abolishes stimulation of interferon production. 2 Publications1
Mutagenesisi390H → A: Strongly reduces stimulation of interferon production. 1 Publication1
Mutagenesisi394K → A: Abolishes enzyme activity. No effect on stimulation of interferon production. 2 Publications1
Mutagenesisi394K → E: Abolishes enzyme activity. Abolishes stimulation of interferon production. 1 Publication1
Mutagenesisi396 – 397CC → AA: Abolishes DNA binding and enzyme activity. Abolishes stimulation of interferon production. 1 Publication2
Mutagenesisi396C → A: Abolishes DNA binding and enzyme activity. 1 Publication1
Mutagenesisi397C → A: Abolishes stimulation of interferon production. 1 Publication1
Mutagenesisi400K → E: Abolishes stimulation of interferon production; when associated with E-403. 1 Publication1
Mutagenesisi403K → E: Abolishes stimulation of interferon production; when associated with E-400. 1 Publication1
Mutagenesisi404C → A: Abolishes stimulation of interferon production. 1 Publication1
Mutagenesisi407K → A or E: Abolishes enzyme activity and stimulation of interferon production; when associated with A-411. Abolishes enzyme activity. Abolishes stimulation of interferon production. 2 Publications1
Mutagenesisi411K → A: Abolishes enzyme activity and stimulation of interferon production; when associated with A-407. 1 Publication1
Mutagenesisi414K → A or E: Abolishes stimulation of interferon production. 1 Publication1
Mutagenesisi436Y → I: Abolishes enzyme activity; when associated with Q-211 and I-376. 1 Publication1

Organism-specific databases

DisGeNETi115004.
OpenTargetsiENSG00000164430.
PharmGKBiPA134956015.

Polymorphism and mutation databases

BioMutaiMB21D1.
DMDMi68565218.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000895431 – 522Cyclic GMP-AMP synthaseAdd BLAST522

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei7N6-acetyllysineCombined sources1
Modified residuei143PhosphoserineCombined sources1
Modified residuei2865-glutamyl polyglutamateBy similarity1
Modified residuei3145-glutamyl glutamateBy similarity1
Modified residuei414N6-acetyllysineCombined sources1

Post-translational modificationi

Polyglutamylated by TTLL6 at Glu-286, leading to impair DNA-binding activity. Monoglutamylated at Glu-314 by TTLL4, leading to impair the nucleotidyltransferase activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6.By similarity
Cleaved by CASP1 at Asp-140 and Asp-157 upon DNA virus infection; the cleavage impairs cGAMP production (PubMed:28314590). Also cleaved by the pyroptotic CASP4 and CASP5 during non-canonical inflammasome activation; they don't cut at the same sites than CASP1 (PubMed:28314590).1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei140 – 141Cleavage; by CASP11 Publication2
Sitei157 – 158Cleavage; by CASP11 Publication2

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein

Proteomic databases

EPDiQ8N884.
MaxQBiQ8N884.
PaxDbiQ8N884.
PeptideAtlasiQ8N884.
PRIDEiQ8N884.

PTM databases

iPTMnetiQ8N884.
PhosphoSitePlusiQ8N884.

Expressioni

Tissue specificityi

Expressed in the monocytic cell line THP1.1 Publication

Inductioni

By type I interferons.1 Publication

Gene expression databases

BgeeiENSG00000164430.
CleanExiHS_C6orf150.
GenevisibleiQ8N884. HS.

Organism-specific databases

HPAiHPA031700.
HPA031702.

Interactioni

Subunit structurei

Monomer in the absence of DNA and when bound to dsDNA.1 Publication

Protein-protein interaction databases

BioGridi125408. 7 interactors.
IntActiQ8N884. 5 interactors.
STRINGi9606.ENSP00000359339.

Structurei

Secondary structure

1522
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi157 – 159Combined sources3
Helixi162 – 174Combined sources13
Turni175 – 178Combined sources4
Helixi180 – 197Combined sources18
Helixi201 – 203Combined sources3
Beta strandi207 – 210Combined sources4
Helixi212 – 216Combined sources5
Beta strandi220 – 222Combined sources3
Beta strandi225 – 233Combined sources9
Beta strandi237 – 242Combined sources6
Beta strandi246 – 254Combined sources9
Helixi263 – 265Combined sources3
Helixi273 – 288Combined sources16
Beta strandi292 – 294Combined sources3
Beta strandi296 – 298Combined sources3
Beta strandi304 – 306Combined sources3
Beta strandi308 – 312Combined sources5
Turni313 – 315Combined sources3
Beta strandi316 – 326Combined sources11
Helixi332 – 334Combined sources3
Turni341 – 344Combined sources4
Helixi346 – 353Combined sources8
Beta strandi357 – 361Combined sources5
Beta strandi375 – 378Combined sources4
Helixi380 – 388Combined sources9
Beta strandi391 – 393Combined sources3
Turni394 – 397Combined sources4
Beta strandi398 – 400Combined sources3
Helixi406 – 423Combined sources18
Helixi425 – 427Combined sources3
Turni429 – 432Combined sources4
Helixi435 – 448Combined sources14
Helixi452 – 455Combined sources4
Helixi457 – 459Combined sources3
Helixi460 – 477Combined sources18
Turni493 – 495Combined sources3
Helixi498 – 513Combined sources16
Helixi518 – 521Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4KM5X-ray2.50A157-522[»]
4LEVX-ray1.95A/B157-522[»]
4LEWX-ray2.04A/B157-522[»]
4MKPX-ray1.95A161-522[»]
4O67X-ray2.44A/B161-522[»]
4O68X-ray2.44A147-522[»]
4O69X-ray2.25A161-522[»]
ProteinModelPortaliQ8N884.
SMRiQ8N884.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 160DNA-binding1 PublicationAdd BLAST160
Regioni120 – 160Required for activation upon DNA viral infection1 PublicationAdd BLAST41
Regioni173 – 215DNA-binding1 PublicationAdd BLAST43
Regioni384 – 407DNA-binding1 PublicationAdd BLAST24

Domaini

The N-terminal part (1-160) binds unspecifically dsDNA and expand the binding and moving range of MB21D1 on dsDNA. Enhances the enzyme activity and activation of innate immune signaling upon cytosolic recognition of dsDNA (PubMed:28363908, PubMed:28214358). When the N-terminal part (1-160) is missing the protein bound to dsDNA homodimerizes (By similarity).By similarity2 Publications

Sequence similaritiesi

Belongs to the mab-21 family.Curated

Phylogenomic databases

eggNOGiENOG410IE27. Eukaryota.
ENOG410XTKD. LUCA.
GeneTreeiENSGT00710000106842.
HOGENOMiHOG000293423.
HOVERGENiHBG068840.
InParanoidiQ8N884.
KOiK17834.
OMAiPQDSQWD.
OrthoDBiEOG091G0MHW.
PhylomeDBiQ8N884.
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.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8N884-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MQPWHGKAMQ RASEAGATAP KASARNARGA PMDPTESPAA PEAALPKAGK
60 70 80 90 100
FGPARKSGSR QKKSAPDTQE RPPVRATGAR AKKAPQRAQD TQPSDATSAP
110 120 130 140 150
GAEGLEPPAA REPALSRAGS CRQRGARCST KPRPPPGPWD VPSPGLPVSA
160 170 180 190 200
PILVRRDAAP GASKLRAVLE KLKLSRDDIS TAAGMVKGVV DHLLLRLKCD
210 220 230 240 250
SAFRGVGLLN TGSYYEHVKI SAPNEFDVMF KLEVPRIQLE EYSNTRAYYF
260 270 280 290 300
VKFKRNPKEN PLSQFLEGEI LSASKMLSKF RKIIKEEIND IKDTDVIMKR
310 320 330 340 350
KRGGSPAVTL LISEKISVDI TLALESKSSW PASTQEGLRI QNWLSAKVRK
360 370 380 390 400
QLRLKPFYLV PKHAKEGNGF QEETWRLSFS HIEKEILNNH GKSKTCCENK
410 420 430 440 450
EEKCCRKDCL KLMKYLLEQL KERFKDKKHL DKFSSYHVKT AFFHVCTQNP
460 470 480 490 500
QDSQWDRKDL GLCFDNCVTY FLQCLRTEKL ENYFIPEFNL FSSNLIDKRS
510 520
KEFLTKQIEY ERNNEFPVFD EF
Length:522
Mass (Da):58,814
Last modified:July 5, 2005 - v2
Checksum:i808FF6F9F3BF8C50
GO
Isoform 2 (identifier: Q8N884-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     445-447: VCT → RLY
     448-522: Missing.

Note: No experimental confirmation available.
Show »
Length:447
Mass (Da):49,762
Checksum:i61504BFBBB6FD338
GO

Sequence cautioni

The sequence AAH12928 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05081135T → N2 PublicationsCorresponds to variant dbSNP:rs9352000Ensembl.1
Natural variantiVAR_033677261P → H1 PublicationCorresponds to variant dbSNP:rs610913Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_014388445 – 447VCT → RLY in isoform 2. 1 Publication3
Alternative sequenceiVSP_014389448 – 522Missing in isoform 2. 1 PublicationAdd BLAST75

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
KC294566 mRNA. Translation: AGB51853.1.
AK097148 mRNA. Translation: BAC04965.1.
AL603910, AC019205 Genomic DNA. Translation: CAI14878.1.
AL603910, AC019205 Genomic DNA. Translation: CAI14879.1.
BC012928 mRNA. Translation: AAH12928.1. Different initiation.
BC108714 mRNA. Translation: AAI08715.1.
BC113606 mRNA. Translation: AAI13607.1.
BC113608 mRNA. Translation: AAI13609.1.
BC143694 mRNA. Translation: AAI43695.1.
CCDSiCCDS4978.1. [Q8N884-1]
RefSeqiNP_612450.2. NM_138441.2. [Q8N884-1]
UniGeneiHs.658405.

Genome annotation databases

EnsembliENST00000370315; ENSP00000359339; ENSG00000164430. [Q8N884-1]
ENST00000370318; ENSP00000359342; ENSG00000164430. [Q8N884-2]
GeneIDi115004.
KEGGihsa:115004.
UCSCiuc003pgx.2. human. [Q8N884-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCGAS_HUMAN
AccessioniPrimary (citable) accession number: Q8N884
Secondary accession number(s): L0L2J9
, Q14CV6, Q32NC9, Q5SWL0, Q5SWL1, Q96E45
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 5, 2005
Last sequence update: July 5, 2005
Last modified: August 30, 2017
This is version 123 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 6
    Human chromosome 6: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families