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1.C.11.1.4
Bifunctional adenylate cyclase-haemolysin toxin precursor, CyaA.  Although homologous, HlyA (1.C.11.1.3) and CyaA  exhibit different modes of permeabilization (Fiser and Konopásek 2009).  A pore model comprising three alpha2-loop-alpha3 hairpins suggested that Gly530XXGly533XXXGly537  in TMS2 could function in toxin oligomerization (Juntapremjit et al. 2015).  Structural integrity of TMSs 1, 2, 3 and 5, but not 4, is important for haemolytic activity, particularly for transmembrane helices 2 and 3 that might form the pore (Powthongchin and Angsuthanasombat 2009). CyaA forms small cation-selective membrane pores that permeabilize cells for potassium efflux, contributing to cytotoxicity of CyaA and eventually provoking colloid-osmotic cell lysis (Wald et al. 2016).  The toxin penetrates myeloid phagocytes expressing the complement receptor 3 and delivers into the cytosol its N-terminal adenylate cyclase enzyme domain (~400 residues). In parallel, the ~1300 residue-long RTX hemolysin moiety of CyaA permeabilizes target cell membranes for efflux of cytosolic potassium ions (Svedova et al. 2016).  Positively-charged side-chains substituted at positions Gln574 and Glu581 in the pore-lining alpha3 enhance hemolytic activity and ion-channel opening, mimicing the highly-active RTX (repeat-in-toxin) cytolysins (Kurehong et al. 2017). Residues 529 to 549 participate in membrane penetration and pore-forming activity (Roderova et al. 2019). Two distinct conformers of CyaA appear to accomplish its two parallel activities within target cell membranes. The translocating conformer would deliver the N-terminal adenylyl cyclase domain into the cytosol of cells, while the pore precursor conformer would assemble into oligomeric cation-selective pores and permeabilize cellular membrane. Both toxin activities involve a membrane-interacting 'AC-to-Hly-linking segment' (residues 400 to 500). Two clusters of negatively charged residues within this linking segment (Glu419 to Glu432 and Asp445 to Glu448) regulate the balance between the AC domain translocating and pore-forming capacities of CyaA as a function of the calcium concentration (Sukova et al. 2020).

Accession Number:P15318
Protein Name:CyaA or Cya
Length:1706
Molecular Weight:177521.00
Species:Bordetella pertussis [520]
Number of TMSs:1
Location1 / Topology2 / Orientation3: Secreted1
Substrate small molecules

Cross database links:

HEGENOM: HBG353287
RefSeq: NP_879578.1   
Entrez Gene ID: 2664492   
Pfam: PF03497    PF00353    PF02382   
BioCyc: BPER257313:BP0760-MONOMER   
KEGG: bpe:BP0760   

Gene Ontology

GO:0005576 C:extracellular region
GO:0005524 F:ATP binding
GO:0005509 F:calcium ion binding
GO:0008294 F:calcium- and calmodulin-responsive adenylat...
GO:0005516 F:calmodulin binding
GO:0006171 P:cAMP biosynthetic process
GO:0019835 P:cytolysis
GO:0019836 P:hemolysis by symbiont of host erythrocytes
GO:0009405 P:pathogenesis

References (9)

[1] “The calmodulin-sensitive adenylate cyclase of Bordetella pertussis: cloning and expression in Escherichia coli.”  Glaser P.et.al.   2897067
[2] “Comparative analysis of the genome sequences of Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica.”  Parkhill J.et.al.   12910271
[3] “Secretion of cyclolysin, the calmodulin-sensitive adenylate cyclase-haemolysin bifunctional protein of Bordetella pertussis.”  Glaser P.et.al.   2905265
[4] “Isolation and characterization of catalytic and calmodulin-binding domains of Bordetella pertussis adenylate cyclase.”  Munier H.et.al.   2007407
[5] “Identification of residues essential for catalysis and binding of calmodulin in Bordetella pertussis adenylate cyclase by site-directed mutagenesis.”  Glaser P.et.al.   2542030
[6] “Functional consequences of single amino acid substitutions in calmodulin-activated adenylate cyclase of Bordetella pertussis.”  Glaser P.et.al.   2050107
[7] “Phylogeny of adenylyl cyclases.”  Danchin A.et.al.   8418825
[8] “Internal lysine palmitoylation in adenylate cyclase toxin from Bordetella pertussis.”  Hackett M.et.al.   7939682
[9] “The conserved lysine 860 in the additional fatty-acylation site of Bordetella pertussis adenylate cyclase is crucial for toxin function independently of its acylation status.”  Basar T.et.al.   10196151
Structure:
1YRT   1YRU   1ZOT   2COL     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MQQSHQAGYA NAADRESGIP AAVLDGIKAV AKEKNATLMF RLVNPHSTSL IAEGVATKGL 
61:	GVHAKSSDWG LQAGYIPVNP NLSKLFGRAP EVIARADNDV NSSLAHGHTA VDLTLSKERL 
121:	DYLRQAGLVT GMADGVVASN HAGYEQFEFR VKETSDGRYA VQYRRKGGDD FEAVKVIGNA 
181:	AGIPLTADID MFAIMPHLSN FRDSARSSVT SGDSVTDYLA RTRRAASEAT GGLDRERIDL 
241:	LWKIARAGAR SAVGTEARRQ FRYDGDMNIG VITDFELEVR NALNRRAHAV GAQDVVQHGT 
301:	EQNNPFPEAD EKIFVVSATG ESQMLTRGQL KEYIGQQRGE GYVFYENRAY GVAGKSLFDD 
361:	GLGAAPGVPS GRSKFSPDVL ETVPASPGLR RPSLGAVERQ DSGYDSLDGV GSRSFSLGEV 
421:	SDMAAVEAAE LEMTRQVLHA GARQDDAEPG VSGASAHWGQ RALQGAQAVA AAQRLVHAIA 
481:	LMTQFGRAGS TNTPQEAASL SAAVFGLGEA SSAVAETVSG FFRGSSRWAG GFGVAGGAMA 
541:	LGGGIAAAVG AGMSLTDDAP AGQKAAAGAE IALQLTGGTV ELASSIALAL AAARGVTSGL 
601:	QVAGASAGAA AGALAAALSP MEIYGLVQQS HYADQLDKLA QESSAYGYEG DALLAQLYRD 
661:	KTAAEGAVAG VSAVLSTVGA AVSIAAAASV VGAPVAVVTS LLTGALNGIL RGVQQPIIEK 
721:	LANDYARKID ELGGPQAYFE KNLQARHEQL ANSDGLRKML ADLQAGWNAS SVIGVQTTEI 
781:	SKSALELAAI TGNADNLKSV DVFVDRFVQG ERVAGQPVVL DVAAGGIDIA SRKGERPALT 
841:	FITPLAAPGE EQRRRTKTGK SEFTTFVEIV GKQDRWRIRD GAADTTIDLA KVVSQLVDAN 
901:	GVLKHSIKLD VIGGDGDDVV LANASRIHYD GGAGTNTVSY AALGRQDSIT VSADGERFNV 
961:	RKQLNNANVY REGVATQTTA YGKRTENVQY RHVELARVGQ LVEVDTLEHV QHIIGGAGND 
1021:	SITGNAHDNF LAGGSGDDRL DGGAGNDTLV GGEGQNTVIG GAGDDVFLQD LGVWSNQLDG 
1081:	GAGVDTVKYN VHQPSEERLE RMGDTGIHAD LQKGTVEKWP ALNLFSVDHV KNIENLHGSR 
1141:	LNDRIAGDDQ DNELWGHDGN DTIRGRGGDD ILRGGLGLDT LYGEDGNDIF LQDDETVSDD 
1201:	IDGGAGLDTV DYSAMIHPGR IVAPHEYGFG IEADLSREWV RKASALGVDY YDNVRNVENV 
1261:	IGTSMKDVLI GDAQANTLMG QGGDDTVRGG DGDDLLFGGD GNDMLYGDAG NDTLYGGLGD 
1321:	DTLEGGAGND WFGQTQAREH DVLRGGDGVD TVDYSQTGAH AGIAAGRIGL GILADLGAGR 
1381:	VDKLGEAGSS AYDTVSGIEN VVGTELADRI TGDAQANVLR GAGGADVLAG GEGDDVLLGG 
1441:	DGDDQLSGDA GRDRLYGEAG DDWFFQDAAN AGNLLDGGDG RDTVDFSGPG RGLDAGAKGV 
1501:	FLSLGKGFAS LMDEPETSNV LRNIENAVGS ARDDVLIGDA GANVLNGLAG NDVLSGGAGD 
1561:	DVLLGDEGSD LLSGDAGNDD LFGGQGDDTY LFGVGYGHDT IYESGGGHDT IRINAGADQL 
1621:	WFARQGNDLE IRILGTDDAL TVHDWYRDAD HRVEIIHAAN QAVDQAGIEK LVEAMAQYPD 
1681:	PGAAAAAPPA ARVPDTLMQS LAVNWR