UniProt functional annotation for P40136



	UniProt functional annotation for P40136

UniProt code: P40136.

Organism: Bacillus anthracis.

Taxonomy: Bacteria; Firmicutes; Bacilli; Bacillales; Bacillaceae; Bacillus; Bacillus cereus group.

Function: Edema factor (EF), which constitutes one of the three proteins composing the anthrax toxin, causes edema in the host (PubMed:6285339, PubMed:2108958, PubMed:11807546). Acts as a calmodulin-dependent adenylyl cyclase by converting ATP to cAMP, leading to dramatic elevation of intracellular cAMP levels in the host, thereby causing edema (PubMed:6285339, PubMed:2108958, PubMed:11807546). EF is not toxic by itself and only acts as a edema factor when associated with protective antigen (PA) to form the edema toxin (EdTx) (PubMed:11553601, PubMed:2108958). Required for the survival of germinated spores within macrophages at the early stages of infection (PubMed:11737637). {ECO:0000269|PubMed:11553601, ECO:0000269|PubMed:11737637, ECO:0000269|PubMed:11807546, ECO:0000269|PubMed:2108958, ECO:0000269|PubMed:6285339}.

Catalytic activity: Reaction=ATP = 3',5'-cyclic AMP + diphosphate; Xref=Rhea:RHEA:15389, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58165; EC=4.6.1.1; Evidence={ECO:0000269|PubMed:11807546, ECO:0000269|PubMed:2108958, ECO:0000269|PubMed:6285339};

Cofactor: Name=Ca(2+); Xref=ChEBI:CHEBI:29108;

Activity regulation: Host calmodulin is an absolute requirement for its activation (PubMed:2114169, PubMed:11807546). Inhibited by ethyl 5- aminopyrazolo[1,5-a]quinazoline-3-carboxylate (PubMed:12676933). {ECO:0000269|PubMed:11807546, ECO:0000269|PubMed:12676933, ECO:0000269|PubMed:2114169}.

Subunit: Interacts (via ATLF domain) with the cleaved form of protective antigen (PA-63) anthrax toxin; interaction is required for EF translocation into the host cytoplasm. {ECO:0000269|PubMed:11553601, ECO:0000269|PubMed:15313199, ECO:0000269|PubMed:32047164, ECO:0000269|PubMed:9398214}.

Subcellular location: Secreted {ECO:0000269|PubMed:3149607}. Host cytoplasm, host cytosol {ECO:0000269|PubMed:1512256}. Note=Translocation into host cytosol is mediated via interaction with the cleaved form of protective antigen (PA-63): following secretion, EF binds via its N-terminal region to the upper rim of the ring-shaped homooligomer (homoheptamer or homooctamer) formed by PA-63 on the host cell membrane (PubMed:32047164). In this PA-63 pre-pore state, the N- terminal segment of EF refolds into an alpha helix engaged in the alpha-clamp of the PA-63 pre-pore (PubMed:32047164, PubMed:32521227). Recruitment to the PA-63 pre-pore enables domain reorganization of EF (PubMed:32521227). Loaded complexes are then endocytosed, followed by a conformational change of oligomerized PA-63 from the pre-pore to pore state, which is triggered by the low pH in the endosome (PubMed:11207582). EF is then unfolded to pass through the PA-63 pore and translocate into the host cytosol (PubMed:32047164). {ECO:0000269|PubMed:11207582, ECO:0000269|PubMed:32047164, ECO:0000269|PubMed:32521227}.

Domain: The N-terminal region contains the ATLF domain responsible for binding to the cleaved form of protective antigen (PA-63) (PubMed:11807546). The C-terminal region contains the calmodulin- dependent activation domain and the catalytic site (PubMed:11807546). This region is composed of three globular domains: CA, CB and a helical domain connected to CA by a linker (PubMed:11807546). The active site lies at the interface of CA and CB (PubMed:11807546). 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 (PubMed:11807546). {ECO:0000269|PubMed:11807546}.

Similarity: Belongs to the adenylyl cyclase class-2 family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Bacillus anthracis.
Taxonomy:		Bacteria; Firmicutes; Bacilli; Bacillales; Bacillaceae; Bacillus; Bacillus cereus group.



Function:		Edema factor (EF), which constitutes one of the three proteins composing the anthrax toxin, causes edema in the host (PubMed:6285339, PubMed:2108958, PubMed:11807546). Acts as a calmodulin-dependent adenylyl cyclase by converting ATP to cAMP, leading to dramatic elevation of intracellular cAMP levels in the host, thereby causing edema (PubMed:6285339, PubMed:2108958, PubMed:11807546). EF is not toxic by itself and only acts as a edema factor when associated with protective antigen (PA) to form the edema toxin (EdTx) (PubMed:11553601, PubMed:2108958). Required for the survival of germinated spores within macrophages at the early stages of infection (PubMed:11737637). {ECO:0000269\|PubMed:11553601, ECO:0000269\|PubMed:11737637, ECO:0000269\|PubMed:11807546, ECO:0000269\|PubMed:2108958, ECO:0000269\|PubMed:6285339}.


Catalytic activity:		Reaction=ATP = 3',5'-cyclic AMP + diphosphate; Xref=Rhea:RHEA:15389, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58165; EC=4.6.1.1; Evidence={ECO:0000269\|PubMed:11807546, ECO:0000269\|PubMed:2108958, ECO:0000269\|PubMed:6285339};
Cofactor:		Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
Activity regulation:		Host calmodulin is an absolute requirement for its activation (PubMed:2114169, PubMed:11807546). Inhibited by ethyl 5- aminopyrazolo[1,5-a]quinazoline-3-carboxylate (PubMed:12676933). {ECO:0000269\|PubMed:11807546, ECO:0000269\|PubMed:12676933, ECO:0000269\|PubMed:2114169}.
Subunit:		Interacts (via ATLF domain) with the cleaved form of protective antigen (PA-63) anthrax toxin; interaction is required for EF translocation into the host cytoplasm. {ECO:0000269\|PubMed:11553601, ECO:0000269\|PubMed:15313199, ECO:0000269\|PubMed:32047164, ECO:0000269\|PubMed:9398214}.
Subcellular location:		Secreted {ECO:0000269\|PubMed:3149607}. Host cytoplasm, host cytosol {ECO:0000269\|PubMed:1512256}. Note=Translocation into host cytosol is mediated via interaction with the cleaved form of protective antigen (PA-63): following secretion, EF binds via its N-terminal region to the upper rim of the ring-shaped homooligomer (homoheptamer or homooctamer) formed by PA-63 on the host cell membrane (PubMed:32047164). In this PA-63 pre-pore state, the N- terminal segment of EF refolds into an alpha helix engaged in the alpha-clamp of the PA-63 pre-pore (PubMed:32047164, PubMed:32521227). Recruitment to the PA-63 pre-pore enables domain reorganization of EF (PubMed:32521227). Loaded complexes are then endocytosed, followed by a conformational change of oligomerized PA-63 from the pre-pore to pore state, which is triggered by the low pH in the endosome (PubMed:11207582). EF is then unfolded to pass through the PA-63 pore and translocate into the host cytosol (PubMed:32047164). {ECO:0000269\|PubMed:11207582, ECO:0000269\|PubMed:32047164, ECO:0000269\|PubMed:32521227}.
Domain:		The N-terminal region contains the ATLF domain responsible for binding to the cleaved form of protective antigen (PA-63) (PubMed:11807546). The C-terminal region contains the calmodulin- dependent activation domain and the catalytic site (PubMed:11807546). This region is composed of three globular domains: CA, CB and a helical domain connected to CA by a linker (PubMed:11807546). The active site lies at the interface of CA and CB (PubMed:11807546). 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 (PubMed:11807546). {ECO:0000269\|PubMed:11807546}.
Similarity:		Belongs to the adenylyl cyclase class-2 family. {ECO:0000305}.