Pertussis Toxin-ATP Complex

A young boy coughing due to pertussis.

introduction

Protussis Toxins is a major virulence factor of Bordetella pertussis that cause whooping cough. Whooping cough, also known as pertusis, is a highly contagious bacterial disease caused by the bacteria Bordetella pertussis. This disease had been characterized by severe cough that has been documented to cause subconjunctival hemorrhages, rib fractures, hernias, fainting and vertebral artery dissection. The pertussis toxin has been characterized as being a AB toxin meaning that there are 2 subunits: A subunit possesses the enzyme activity and the B subunit it the receptor binding portion. Together this AB toxin colonizes the respiratory tract and becomes activated by destabilization due to the binding of ATP.

structure

The protussis toxin is a AB5 toxin consisting of a six-component protein complex. With that in mind, this protein is a hexamer containing a catalytic (S1) subunit that is tightly associated with the pentameric cell-binding component (B-oligomer). The S1 component is a single subunit while the B-oligomer is a pentamer composed of four types of subunits: , , two copies of , and </scene>.^[1] This B subnit is what binds to the terminal sialic acid residues.

Pertussis Toxin activation

Pertussis Toxin by itself is harmless unless activated. From studies, it has became clear that there is a direct interaction between ATP and pertussis toxin which leads to activation. The direct effect of ATP is to destabilize the interaction between the S1 subunit and the B-oligomer by binding to the B-oligomer. This then relaxes the toxin by facilitating the subsequent reduction of a disulphide bond in the S1 subunit. The main interaction that leads to the destabilization is the favorable hydrogen bonding and electrostatic interaction between the triphosphate moiety and five positively charged amino acids:. In contrast, the negatively charged carboxyl terminus of subunit S1 interacts unfavorably with the negative charges of the triphosphate moiety, causing a displacement of the C-terminal of therefore, the repulsion between the triphosphate moiety and the C terminus of subunit S1 forms the mechanism by which the interaction between S1 and the B-Oligomer is destabilized.

Mechanism of pathogenesis

Following the pertussis toxin binding to the cell membrane, the toxin is taken up by an endosome and transported from the plasma membrane via the Golgi apparatus to the endoplasmic reticulum (ER) where finally membrane translocation occurs. The destabilization of PT occurs in the ER prior to membrane translocation. After binding of ATP, cleavage of the single disulphide bond in subunit S1 is believed to trigger a conformational change necessary to expose the active site to its substrates. The reducation step takes place after interaction of PT with ATP. After destabilization, the S1 becomes active and catalyzes the ADP-ribosylation of the alpa-subunit of regulatory trimeric G-proteins (Gialpha). This then prevents Gialpha from inhibiting adenylate cyclase and leads to an increase in intracellular levels of cyclic AMP (cAMP). The increase in cAMP affects normal biological signaling and causes severe effects such as hypoglycemia.

Conclusion

This paper was significant since it gave a clear understanding of the PT activation as well as a better understanding to the pathogenesis of the toxin. (talk about this more and clarify)