Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

P40136 (CYAA_BACAN) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 132. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Calmodulin-sensitive adenylate cyclase

EC=4.6.1.1
Alternative name(s):
ATP pyrophosphate-lyase
Adenylyl cyclase
Anthrax edema toxin adenylate cyclase component
Edema factor
Short name=EF
Gene names
Name:cya
Ordered Locus Names:pXO1-122, BXA0141, GBAA_pXO1_0142
Encoded onPlasmid pXO1
OrganismBacillus anthracis [Reference proteome] [HAMAP]
Taxonomic identifier1392 [NCBI]
Taxonomic lineageBacteriaFirmicutesBacilliBacillalesBacillaceaeBacillusBacillus cereus group

Protein attributes

Sequence length800 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. EF is a calmodulin-dependent adenylyl cyclase that, when associated with PA, causes edema. EF is not toxic by itself and it is required for the survival of germinated spores within macrophages at the early stages of infection. Provokes dramatic elevation of intracellular cAMP levels in the host.

Catalytic activity

ATP = 3',5'-cyclic AMP + diphosphate.

Cofactor

Calcium.

Enzyme regulation

It has an absolute requirement for host calmodulin for its activation. Inhibited by ethyl 5-aminopyrazolo[1,5-a]quinazoline-3-carboxylate.

Subunit structure

Anthrax toxins are composed of three distinct proteins, a protective antigen (PA), a lethal factor (LF) and an edema factor (EF). None of these is toxic by itself. PA+LF forms the lethal toxin (LeTx); PA+EF forms the edema toxin (EdTx). EF probably forms oligomers as part of the translocation machinery, formed by a heterocomplex of PA63 monomers and EF subunits, and it is functional as a monomer in the host cell.

Subcellular location

Secreted.

Domain

The N-terminal region contains the residues responsible for binding to PA63. The C-terminal region contains the calmodulin-dependent activation domain and the catalytic site. This region is composed of three globular domains: CA, CB and a helical domain connected to CA by a linker. The active site lies at the interface of CA and CB. The metal ion is coordinated by residues from CA; calmodulin probably binds in a multistep fashion first to residues in CA and then to residues present in the linker and the helical domain. Ref.11

The PA-binding region is found in both B.anthracis EF and LF. Ref.11

Miscellaneous

EF binds to the heptamer formed by cleaved PA on the host cell membrane. This step is followed by internalization of the hetero-oligomeric complex by receptor-mediated endocytosis. EF requires passage through an acidic vesicle for activity. At acidic pH, the pore is inserted into the membrane, allowing translocation of EF, which probably contributes actively to its own insertion into the membrane. EF remains associated to the vesicle membrane after translocation to the cytosol, with the catalytic domains being exposed on the cytoplasmic face.

Sequence similarities

Belongs to the adenylyl cyclase class-2 family.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

calm2P621552EBI-457011,EBI-397568From a different organism.
CALM3P621588EBI-457011,EBI-397435From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3333 Ref.2
Chain34 – 800767Calmodulin-sensitive adenylate cyclase
PRO_0000001317

Regions

Region34 – 290257Interaction with protective antigen
Region294 – 34956Catalytic CA1
Region350 – 489140Catalytic CB
Region490 – 622133Catalytic CA2
Region623 – 800178Interaction with calmodulin

Sites

Active site3511Proton acceptor
Metal binding4911Magnesium
Metal binding4931Magnesium

Experimental info

Mutagenesis1691V → A: No effect. Ref.16
Mutagenesis1701Y → A: Loss of cytotoxicity due to inability to bind PA. Ref.16
Mutagenesis1711Y → A: Loss of cytotoxicity due to inability to bind PA. Ref.16
Mutagenesis1721E → A: No effect. Ref.16
Mutagenesis1731I → A: Loss of cytotoxicity due to inability to bind PA. Ref.16
Mutagenesis1741G → A: No effect. Ref.16
Mutagenesis1751K → A: Loss of cytotoxicity due to inability to bind PA. Ref.16
Mutagenesis3291R → M: Great decrease in activity. Ref.17
Mutagenesis3461K → M or R: Loss of activity. Ref.14 Ref.15
Mutagenesis3461K → Q: Loss of activity due to inability to bind the substrate. Ref.14 Ref.15
Mutagenesis3531K → M, R or A: Loss of activity. Ref.14
Mutagenesis4361E → Q: Decreases activity. Ref.14
Mutagenesis4431E → Q: Decreases activity. Ref.17
Mutagenesis4911D → N: Great decrease in activity. Ref.17
Mutagenesis4931D → N: Great decrease in activity. Ref.17
Mutagenesis5231L → A: Little effect on activation by calmodulin.
Mutagenesis5251K → A: Great decrease in calmodulin binding.
Mutagenesis5261Q → A: Little effect on activation by calmodulin.
Mutagenesis5291V → A: Little effect on activation by calmodulin.
Mutagenesis5771H → N or D: Loss of function.
Mutagenesis5831N → A: Decreases activity.
Mutagenesis5831N → Q or H: Loss of function.
Mutagenesis5881E → A: Loss of function.
Mutagenesis5901D → A: Decreases activity.
Mutagenesis6391N → A: Decreases catalysis rate.
Mutagenesis6471D → A: Decreases activity due to reduced activation by calmodulin.
Sequence conflict3501V → E in AAA79215. Ref.2
Sequence conflict5101Q → T AA sequence Ref.2
Sequence conflict512 – 5132EW → RM AA sequence Ref.2
Sequence conflict7601V → L in CAA00652. Ref.3

Secondary structure

....................................................................................................................................... 800
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P40136 [UniParc].

Last modified February 1, 1995. Version 1.
Checksum: F4F7EB485DF4C5A6

FASTA80092,478
        10         20         30         40         50         60 
MTRNKFIPNK FSIISFSVLL FAISSSQAIE VNAMNEHYTE SDIKRNHKTE KNKTEKEKFK 

        70         80         90        100        110        120 
DSINNLVKTE FTNETLDKIQ QTQDLLKKIP KDVLEIYSEL GGEIYFTDID LVEHKELQDL 

       130        140        150        160        170        180 
SEEEKNSMNS RGEKVPFASR FVFEKKRETP KLIINIKDYA INSEQSKEVY YEIGKGISLD 

       190        200        210        220        230        240 
IISKDKSLDP EFLNLIKSLS DDSDSSDLLF SQKFKEKLEL NNKSIDINFI KENLTEFQHA 

       250        260        270        280        290        300 
FSLAFSYYFA PDHRTVLELY APDMFEYMNK LEKGGFEKIS ESLKKEGVEK DRIDVLKGEK 

       310        320        330        340        350        360 
ALKASGLVPE HADAFKKIAR ELNTYILFRP VNKLATNLIK SGVATKGLNV HGKSSDWGPV 

       370        380        390        400        410        420 
AGYIPFDQDL SKKHGQQLAV EKGNLENKKS ITEHEGEIGK IPLKLDHLRI EELKENGIIL 

       430        440        450        460        470        480 
KGKKEIDNGK KYYLLESNNQ VYEFRISDEN NEVQYKTKEG KITVLGEKFN WRNIEVMAKN 

       490        500        510        520        530        540 
VEGVLKPLTA DYDLFALAPS LTEIKKQIPQ KEWDKVVNTP NSLEKQKGVT NLLIKYGIER 

       550        560        570        580        590        600 
KPDSTKGTLS NWQKQMLDRL NEAVKYTGYT GGDVVNHGTE QDNEEFPEKD NEIFIINPEG 

       610        620        630        640        650        660 
EFILTKNWEM TGRFIEKNIT GKDYLYYFNR SYNKIAPGNK AYIEWTDPIT KAKINTIPTS 

       670        680        690        700        710        720 
AEFIKNLSSI RRSSNVGVYK DSGDKDEFAK KESVKKIAGY LSDYYNSANH IFSQEKKRKI 

       730        740        750        760        770        780 
SIFRGIQAYN EIENVLKSKQ IAPEYKNYFQ YLKERITNQV QLLLTHQKSN IEFKLLYKQL 

       790        800 
NFTENETDNF EVFQKIIDEK 

« Hide

References

« Hide 'large scale' references
[1]"Structural homology between virulence-associated bacterial adenylate cyclases."
Escuyer V., Duflot E., Sezer O., Danchin A., Mock M.
Gene 71:293-298(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]"Nucleotide sequence of the Bacillus anthracis edema factor gene (cya): a calmodulin-dependent adenylate cyclase."
Robertson D.L., Tippetts M.T., Leppla S.H.
Gene 73:363-371(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], PROTEIN SEQUENCE OF 34-48.
[3]"Nucleotide sequences expressing adenylate cyclase from B.anthracis, proteins having the activity of this adenylate cyclase and biological uses."
Escuyer V., Duflot E., Mock M., Danchin A.
Patent number EP0366550, 02-MAY-1990
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"Molecular cloning and expression of the Bacillus anthracis edema factor toxin gene: a calmodulin-dependent adenylate cyclase."
Tippetts M.T., Robertson D.L.
J. Bacteriol. 170:2263-2266(1988) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]"Sequence and organization of pXO1, the large Bacillus anthracis plasmid harboring the anthrax toxin genes."
Okinaka R.T., Cloud K., Hampton O., Hoffmaster A.R., Hill K.K., Keim P., Koehler T.M., Lamke G., Kumano S., Mahillon J., Manter D., Martinez Y., Ricke D., Svensson R., Jackson P.J.
J. Bacteriol. 181:6509-6515(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: Sterne.
[6]"Comparative genome sequencing for discovery of novel polymorphisms in Bacillus anthracis."
Read T.D., Salzberg S.L., Pop M., Shumway M.F., Umayam L., Jiang L., Holtzapple E., Busch J.D., Smith K.L., Schupp J.M., Solomon D., Keim P., Fraser C.M.
Science 296:2028-2033(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Strain: Ames / isolate Florida / A2012.
[7]"The complete genome sequence of Bacillus anthracis Ames 'Ancestor'."
Ravel J., Jiang L., Stanley S.T., Wilson M.R., Decker R.S., Read T.D., Worsham P., Keim P.S., Salzberg S.L., Fraser-Liggett C.M., Rasko D.A.
J. Bacteriol. 191:445-446(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: Ames ancestor.
[8]"Sequence analysis of the genes encoding for the major virulence factors of Bacillus anthracis vaccine strain 'Carbosap'."
Adone R., Pasquali P., La Rosa G., Marianelli C., Muscillo M., Fasanella A., Francia M., Ciuchini F.
J. Appl. Microbiol. 93:117-121(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-783.
Strain: Carbosap and Ferrara.
[9]"Structure and interaction of PA63 and EF (edema toxin) of Bacillus anthracis with lipid membrane."
Wang X.-M., Wattiez R., Mock M., Falmagne P., Ruysschaert J.-M., Cabiaux V.
Biochemistry 36:14906-14913(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
Strain: Sterne.
[10]"Translocation of Bacillus anthracis lethal and oedema factors across endosome membranes."
Guidi-Rontani C., Weber-Levy M., Mock M., Cabiaux V.
Cell. Microbiol. 2:259-264(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
Strain: Sterne.
[11]"Characterization of ATP and calmodulin-binding properties of a truncated form of Bacillus anthracis adenylate cyclase."
Labruyere E., Mock M., Ladant D., Michelson S., Gilles A.-M., Laoide B., Barzu O.
Biochemistry 29:4922-4928(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF CALMODULIN-BINDING DOMAIN.
[12]"Fate of germinated Bacillus anthracis spores in primary murine macrophages."
Guidi-Rontani C., Levy M., Ohayon H., Mock M.
Mol. Microbiol. 42:931-938(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: EFFECT ON SPORE GERMINATION.
Strain: Sterne.
[13]"Structure-based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough."
Soelaiman S., Wei B.Q., Bergson P., Lee Y.-S., Shen Y., Mrksich M., Shoichet B.K., Tang W.-J.
J. Biol. Chem. 278:25990-25997(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INHIBITION BY QUINAZOLINE COMPOUNDS.
[14]"A-type ATP binding consensus sequences are critical for the catalytic activity of the calmodulin-sensitive adenylyl cyclase from Bacillus anthracis."
Xia Z., Storm D.R.
J. Biol. Chem. 265:6517-6520(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF LYS-346; LYS-353 AND GLU-436.
Strain: SRI-1.
[15]"Structural and ligand-binding properties of a truncated form of Bacillus anthracis adenylate cyclase and of a catalytically inactive variant in which glutamine substitutes for lysine-346."
Labruyere E., Mock M., Surewicz W.K., Mantsch H.H., Rose T., Munier H., Sarfati R.S., Barzu O.
Biochemistry 30:2619-2624(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF LYS-346.
Strain: Sterne.
[16]"Purification of anthrax edema factor from Escherichia coli and identification of residues required for binding to anthrax protective antigen."
Kumar P., Ahuja N., Bhatnagar R.
Infect. Immun. 69:6532-6536(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF VAL-169; TYR-170; TYR-171; GLU-172; ILE-173; GLY-174 AND LYS-175.
[17]"An extended conformation of calmodulin induces interactions between the structural domains of adenylyl cyclase from Bacillus anthracis to promote catalysis."
Drum C.L., Yan S.-Z., Sarac R., Mabuchi Y., Beckingham K., Bohm A., Grabarek Z., Tang W.-J.
J. Biol. Chem. 275:36334-36340(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ARG-329; GLU-443; ASP-491 AND ASP-493.
[18]"Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin."
Drum C.L., Yan S.-Z., Bard J., Shen Y.-Q., Lu D., Soelaiman S., Grabarek Z., Bohm A., Tang W.-J.
Nature 415:396-402(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS), MUTAGENESIS.
[19]"Phylogeny of adenylyl cyclases."
Danchin A.
Adv. Second Messenger Phosphoprotein Res. 27:109-162(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[20]"Anthrax."
Mock M., Fouet A.
Annu. Rev. Microbiol. 55:647-671(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M23179 Genomic DNA. Translation: AAA22374.1.
M24074 Genomic DNA. Translation: AAA79215.1.
A07289 Unassigned DNA. Translation: CAA00652.1. Sequence problems.
AF065404 Genomic DNA. Translation: AAD32426.1.
AE011190 Genomic DNA. Translation: AAM26089.1.
AE017336 Genomic DNA. Translation: AAT28883.2.
AJ413930 Genomic DNA. Translation: CAC93924.1.
AJ413931 Genomic DNA. Translation: CAC93925.1.
PIRB59106.
JS0029.
RefSeqNP_052818.1. NC_001496.1.
NP_652900.1. NC_003980.1.
YP_016473.2. NC_007322.2.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1K8TX-ray2.60A291-800[»]
1K90X-ray2.75A/B/C291-800[»]
1K93X-ray2.95A/B/C291-800[»]
1LVCX-ray3.60A/B/C291-800[»]
1PK0X-ray3.30A/B/C292-798[»]
1S26X-ray3.00A/B/C291-800[»]
1SK6X-ray3.20A/B/C291-800[»]
1XFUX-ray3.35A/B/C/D/E/F64-800[»]
1XFVX-ray3.35A/B/C/D/E/F33-800[»]
1XFWX-ray3.40A/B/C/D/E/F33-800[»]
1XFXX-ray3.20A/B/C/D/E/F33-800[»]
1XFYX-ray3.30A/B/C/D/E/F33-800[»]
1XFZX-ray3.25A/B/C/D/E/F33-800[»]
1Y0VX-ray3.60A/B/C/D/E/F33-800[»]
DisProtDP00395.
ProteinModelPortalP40136.
SMRP40136. Positions 64-798.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-31055N.
IntActP40136. 3 interactions.
STRING261594.GBAA_pXO1_0142.

Chemistry

BindingDBP40136.
ChEMBLCHEMBL5396.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblBacteriaAAT28883; AAT28883; GBAA_pXO1_0142.
GeneID1158701.
2820138.
3361726.
KEGGbar:GBAA_pXO1_0142.
PATRIC24662079. VBIBacAnt106580_0129.

Phylogenomic databases

eggNOGNOG146287.
HOGENOMHOG000034573.
KOK11029.
OMADKFEVFQ.
OrthoDBEOG62ZHV6.

Enzyme and pathway databases

BioCycANTHRA:GBAA_PXO1_0142-MONOMER.
BANT261594:GJ7F-5728-MONOMER.

Family and domain databases

Gene3D3.40.390.10. 1 hit.
InterProIPR005165. Anthrax_toxin_edema_cen.
IPR003541. Anthrax_toxin_lethal/edema.
IPR014781. Anthrax_toxin_lethal/edema_N/C.
IPR024079. MetalloPept_cat_dom.
[Graphical view]
PfamPF03497. Anthrax_toxA. 1 hit.
PF07737. ATLF. 1 hit.
[Graphical view]
PRINTSPR01392. ANTHRAXTOXNA.
ProtoNetSearch...

Other

EvolutionaryTraceP40136.

Entry information

Entry nameCYAA_BACAN
AccessionPrimary (citable) accession number: P40136
Secondary accession number(s): Q937W4, Q937W5
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: June 11, 2014
This is version 132 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programProkaryotic Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references