Bifunctional hemolysin/adenylate cyclase is a protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that in B. pertussis

Bordetella pertussis

Bordetella pertussis is a Gram-negative, aerobic coccobacillus of the genus Bordetella, and the causative agent of pertussis or whooping cough. Unlike B. bronchiseptica, B. pertussis is non-motile. Its virulence factors include pertussis toxin, filamentous hæmagglutinin, pertactin, fimbria, and...

(the bacteria that causes whooping cough

Pertussis

Pertussis, also known as whooping cough , is a highly contagious bacterial disease caused by Bordetella pertussis. Symptoms are initially mild, and then develop into severe coughing fits, which produce the namesake high-pitched "whoop" sound in infected babies and children when they inhale air...

) is encoded by the cyaA gene

Gene

A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

. This protein in turn is cleaved into a calmodulin

Calmodulin

Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...

-sensitive adenylate cyclase

Adenylate cyclase

Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....

 (cyaA–ACD) and hemolysin

Hemolysin

Hemolysins are exotoxins produced by bacteria that cause lysis of red blood cells in vitro. Visualization of hemolysis of red blood cells in agar plates facilitates the categorization of some pathogenic bacteria such as Streptococcus and Staphylococcus...

. Both are virulence factors facilitating respiratory tract colonization by B. pertussis. The cyaA–ACD binds to a M2 integrin cell surface receptor

Macrophage-1 antigen

Macrophage-1 antigen is a complement receptor consisting of CD11b and CD18.It binds to C3b and C4b.-Function:...

 and inserts its N-terminal adenylyl cyclase domain into the cytosol

Cytosol

The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

. After binding to calmodulin, cyaA–ACD catalyzes the cyclization of AMP

Adenosine monophosphate

Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...

 into cAMP

Cyclic adenosine monophosphate

Cyclic adenosine monophosphate is a second messenger important in many biological processes...

. This catalysis raises the intracellular concentration of cAMP to toxic levels.

Structure

Four discrete regions of CyaA bind calcium-loaded calmodulin with a large buried contact surface. Of those, a tryptophan residue (W242) at an alpha-helix of CyaA makes extensive contacts with the calcium-induced, hydrophobic pocket of calmodulin. Mutagenic analyses show that all four regions of CyaA contribute to calmodulin binding and the calmodulin-induced conformational change of CyaA is crucial for catalytic activation. A crystal structure of CyaA-calmodulin with adefovir diphosphate, the metabolite of an approved antiviral drug, reveals the location of catalytic site of CyaA and how adefovir diphosphate tightly binds CyaA. The ACD of CyaA shares a similar structure and mechanism of activation with anthrax edema factor (EF). However, the interactions of CyaA with calmodulin completely diverge from those of EF. This provides molecular details of how two structurally homologous bacterial toxins evolved divergently to bind calmodulin, an evolutionarily conserved calcium sensor.

Chemistry

CyaA binds to calcium ions selectively and non-covalently, along with other proteins and protein complexes. It has also been shown to interact with one or more specific sites on a receptor molecule, a macromolecule that combines with a hormone, neurotransmitter, drug, or intracellular messenger to initiate a change in cell function.