Pertussis Toxin-ATP Complex: Difference between revisions

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Jonathan Tringali, Jaime Prilusky, Michal Harel

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 ==Mechanism of pathogenesis==
-Following the pertussis toxin binding to the cell membrane (B subunit binds to terminal sialic acid residues), 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 by [http://en.wikipedia.org/wiki/Protein_disulfide_isomerase protein disulphide isomerase] (PDI) occurs in subunit S1 <scene name='Pertussis_Toxin-ATP_Complex/Disulphide_bonds_breaking/1'>(Cys 41-Cys 201)</scene> and 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 [http://en.wikipedia.org/wiki/ADP_ribosylation ADP-ribosylation] of the alpa-subunit of regulatory trimeric [http://en.wikipedia.org/wiki/G_proteins G-proteins] (Giα).  This then prevents Giα from inhibiting adenylate cyclase and leads to an increase in intracellular levels of [http://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate Cyclic adenosine monophosphate] (cAMP).  The increase in cAMP affects normal biological signaling and causes severe effects such as hypoglycemia.
+The disease pertussis has two stages.  The first stage is colonization of the upper respiratory tract where ''B. pertussis'' adheres by using filamentous hemagglutinin (FHA) and cell bound pertussis toxin PTx.  This can be visualized in the following image of [http://www.proteopedia.org/wiki/images/3/3e/B.pertussis.jpeg the colonization of tracheal epithelial cells by ''Bordetella pertussis'' ]
+The second stage is the toxemic stage which follows the colonization stage.  The PT B subunit oligomer uses cell-bound toxin (S2 and S3) as adhesins, and they  bind the bacteria to host cells. S2 and S3 utilize different receptors on host cells. S2 binds specifically to a glycolipid, which is found primarily on the ciliated epithelial cells. S3 binds to a glycoprotein found mainly on phagocytic cells.  After binding, 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 by [http://en.wikipedia.org/wiki/Protein_disulfide_isomerase protein disulphide isomerase] (PDI) occurs in subunit S1 <scene name='Pertussis_Toxin-ATP_Complex/Disulphide_bonds_breaking/1'>(Cys 41-Cys 201)</scene> and 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 [http://en.wikipedia.org/wiki/ADP_ribosylation ADP-ribosylation] of the alpa-subunit of regulatory trimeric [http://en.wikipedia.org/wiki/G_proteins G-proteins] (Giα) host protein.  This then prevents Giα from inhibiting adenylate cyclase and leads to an increase in intracellular levels of [http://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate Cyclic adenosine monophosphate] (cAMP).  The conversion of ATP to cyclic AMP cannot be stopped and intracellular levels of cAMP increase.  This has the effect to disrupt cellular function/signaling, and in the case of phagocytes, to decrease their phagocytic activities such as chemotaxis, engulfment, the oxidative burst, and bacteridcidal killing.
 ==Treatment==