Pertussis Toxin-ATP Complex: Difference between revisions

The pertussis toxin has been characterized, as being an AB toxin meaning that there are 2 subunits: A subunit possesses the enzyme activity and the B subunit it the receptor binding portion.  PT in particular is an 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 <scene name='Pertussis_Toxin-ATP_Complex/Subunit_1/3'>S1 (chains A,G)</scene> while the B-oligomer is a pentamer composed of four types of subunits: <scene name='Pertussis_Toxin-ATP_Complex/Subunit_2/3'>S2 (chains B,H)</scene>,  

'''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:<scene name='Pertussis_Toxin-ATP_Complex/5_amino_acid_interaction/2'>Arg S2:150, Lys S2-151, Arg S3-150, and Arg S4b-69</scene>. 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 <scene name='Pertussis_Toxin-ATP_Complex/Repulsion_of_subunit_s1/3'>Tyr 233:A and Phe 235:A</scene>  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.

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 <scene name='Pertussis_Toxin-ATP_Complex/Disulphide_bonds_breaking/1'>(Cys 41-Cys 201)</scene> 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.

Early treatment of pertussis is the only effective way to treat the bacterial infection.  If treatment for pertussis is started early in the course of illness during the 1 to 2 weeks before severe coughing occurs, the symptoms may be lessened.  If the diagnosed to late, antibiotics will not alter the course of the illness since the bacteria is already producing the PT toxin.  The preferred antibiotics are Erythromycin, clarithromycin, and azithromycin.