Pertussis Toxin-ATP Complex: Difference between revisions
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<StructureSection load=1bcp size='500' side='right' caption='Pertussis Toxin-ATP complex ([[1bcp]])' scene=''>[[Image:230px-Pertussis.jpg|left|thumb|A young boy coughing due to pertussis.]] | <StructureSection load=1bcp size='500' side='right' caption='Pertussis Toxin-ATP complex ([[1bcp]])' scene=''>[[Image:230px-Pertussis.jpg|left|thumb|A young boy coughing due to pertussis.]] | ||
==Introduction== | ==Introduction== | ||
'''Pertussis Toxins''' (PT) is a protein-based exotoxin and major virulence factor produced by the bacterium [http://en.wikipedia.org/wiki/Bordetella_pertussis ''Bordetella pertussis''].<ref name=Hazes>PMID: 8637000</ref> PT causes [http://en.wikipedia.org/wiki/Whooping_cough pertussis], which is also known at whooping cough and is highly contagious bacterial disease. The disease is caused by the bacterium colonizing the respiratory tract where it then establishes an infection. | '''Pertussis Toxins''' (PT) is a protein-based exotoxin and major virulence factor produced by the bacterium [http://en.wikipedia.org/wiki/Bordetella_pertussis ''Bordetella pertussis''].<ref name=Hazes>PMID: 8637000</ref> PT causes [http://en.wikipedia.org/wiki/Whooping_cough pertussis], which is also known at whooping cough and is highly contagious bacterial disease. The disease is caused by the bacterium colonizing the respiratory tract where it then establishes an infection.<ref name=Carbonetti>PMID: 14573656</ref> This disease had been characterized by severe coughing that can last up to six weeks and in some countries lasting nearly 100 days.<ref name=Carbonetti>PMID: 17418639</ref>It has been documented in some cases that PT can cause [http://en.wikipedia.org/wiki/Subconjunctival_hemorrhage subconjunctival hemorrhages], [http://en.wikipedia.org/wiki/Rib_fracture rib fractures], [http://en.wikipedia.org/wiki/Hernias hernias], fainting and [http://en.wikipedia.org/wiki/Vertebral_artery_dissection vertebral artery dissection].<ref name=cornia>PMID: 20736473</ref> | ||
As of 2010, the worldwide incidence of whooping cough has been estimated to 48.5 million cases and nearly 295,000 deaths per year.<ref name=Bettiol>PMID: 20091541</ref> With that in mind, whooping cough can affect people of any age; however, before vaccines were available the disease was most common in infants and young children but now children are immunized and the high percentage of cases are seen among adolescents. | As of 2010, the worldwide incidence of whooping cough has been estimated to 48.5 million cases and nearly 295,000 deaths per year.<ref name=Bettiol>PMID: 20091541</ref> With that in mind, whooping cough can affect people of any age; however, before vaccines were available the disease was most common in infants and young children but now children are immunized and the high percentage of cases are seen among adolescents. | ||
==Structure== | ==Structure== | ||
The [http://en.wikipedia.org/wiki/Pertussis_toxin 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 possesses it the receptor binding portion. PT in particular is an AB5 toxin consisting of a six-component protein complex, and the multiple subunits of the complex are not identical in composition. | The [http://en.wikipedia.org/wiki/Pertussis_toxin 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 possesses it the receptor binding portion. PT in particular is an AB5 toxin consisting of a six-component protein complex, and the multiple subunits of the complex are not identical in composition.<ref name=Hazes>PMID: 8637000</ref> 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).<ref name=Hazes>PMID: 8637000</ref> 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>, <scene name='Pertussis_Toxin-ATP_Complex/Subunit_3/5'>S3 (chains C,I)</scene>, two copies of <scene name='Pertussis_Toxin-ATP_Complex/Subunit_4/3'>S4 (chains D,E,J,K)</scene>, and <scene name='Pertussis_Toxin-ATP_Complex/Subunit_5/4'>S5 (chains F,L)</scene>.<ref name=Hazes>PMID: 8637000</ref> The overall structure of PT <scene name='Pertussis_Toxin-ATP_Complex/Whole_monomer/1'>multisubunit complex</scene>. These subunits are encoded by ptx genes, which are encoded on a large PT [http://en.wikipedia.org/wiki/Operon operon] that includes additional genes as well such as Pti genes. Together the PT and Pti proteins form the PT secretion complex and toxin itself.<ref name=Weiss>PMID: 8464913</ref> | ||
==Pertussis Toxin activation== | ==Pertussis Toxin activation== | ||
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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 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. | 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.<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. 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.<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> | 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.<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> | ||