Pertussis Toxin-ATP Complex: Difference between revisions

← Older edit Newer edit →

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Jonathan Tringali, Jaime Prilusky, Michal Harel

@@ Line 16: / Line 16: @@
 <ref>Kenneth Todar, PhD. (2008). http://www.textbookofbacteriology.net/pertussis.html</ref>
-The second stage is the toxemic stage which follows the colonization stage.  The PT B subunit oligomer uses S2 and S3 as adhesins, and they  bind the bacteria to host cell receptors. 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.<ref name=Hazes>PMID: 8637000</ref> The reducation step takes place after interaction of PT with ATP.
+The second stage is the toxemic stage which follows the colonization stage.  The PT B subunit oligomer uses S2 and S3 as adhesins, and they  bind the bacteria to host cell receptors. 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.<ref name=Plaut>PMID: 18201245</ref>  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.<ref name=Hazes>PMID: 8637000</ref> 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.<ref name=Hazes>PMID: 8637000</ref><ref name=Kaslow>PMID: 1612292</ref> This then prevents Giα from inhibiting [http://en.wikipedia.org/wiki/Adenylate_cyclase 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 [http://proteopedia.org/wiki/images/b/bb/500px-Adenylate_kinase.png ATP to cyclic AMP] cannot be stopped and intracellular levels of cAMP increase.<ref>Kenneth Todar, PhD. (2008). http://www.textbookofbacteriology.net/pertussis.html</ref>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.<ref>Kenneth Todar, PhD. (2008). http://www.textbookofbacteriology.net/pertussis.html</ref>