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This subunit catalyzes '''ADP-ribosylation''' of the ''α-subunit of trimeric G proteins'', which disturbs functions of the target cells and therefore lead to various biological effects. | This subunit catalyzes '''ADP-ribosylation''' of the ''α-subunit of trimeric G proteins'', which disturbs functions of the target cells and therefore lead to various biological effects. | ||
In facts, substrates of PTX are regulators of the membrane-bound adenylate cyclase. These G proteins bind GTP in order to transduce signals in the cell. When ADP-ribosylation by PTX occurs, ''the downregulation of the adenylate cyclase activity is inhibited''. | In facts, substrates of PTX are regulators of the membrane-bound adenylate cyclase. These G proteins bind GTP in order to transduce signals in the cell. When ADP-ribosylation by PTX occurs, ''the downregulation of the adenylate cyclase activity is inhibited''. This inhibition leads to increase cAMP levels in cells, which explains the amount of biological activities of the toxin. | ||
This inhibition leads to increase cAMP levels in cells, which explains the amount of biological activities of the toxin. | |||
-> picture of the active site of the S1 subunit <br /> | -> picture of the active site of the S1 subunit <br /> | ||
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labeled in blue : catalytic residues (His35, Glu129) <br /> | labeled in blue : catalytic residues (His35, Glu129) <br /> | ||
The ADP-ribosylation of trimeric G proteins occurs on a ''' | The ADP-ribosylation of trimeric G proteins occurs on a '''cysteine residue''' in the ''C-terminal part of the α-subunit''. <br /> | ||
For that, the donor substrate used by PTX is '''NAD<sup>+</sup>''', which binds the toxin through '''Trp26''', '''Arg9''' and '''Cys41''' located in the ''active site of S1''. <br /> | For that, the donor substrate used by PTX is '''NAD<sup>+</sup>''', which binds the toxin through '''Trp26''', '''Arg9''' and '''Cys41''' located in the ''active site of S1''. <br /> | ||
Concerning the acceptor substrate, it binds to the toxin through '''residues 180-219''' in the ''C-terminal region of S1''. These residues show indeed a high affinity for the G protein and are involved in the catalysis of the ADP-ribosylation. | Concerning the acceptor substrate, it binds to the toxin through '''residues 180-219''' in the ''C-terminal region of S1''. These residues show indeed a high affinity for the G protein and are involved in the catalysis of the ADP-ribosylation. <br /> | ||
In the S1 subunit, the ''catalytic residues'' '''His35''' and '''Glu129''' have been identified : His35 is involved in the ionization of the nucleophilic thiol of the cysteine residue in the G protein via its ε-N and the carboxylate group of the Glu129 side chain is in contact with the 2'-ribo-hydroxyl of the NAD<sup>+</sup>. | |||
==Toxic effects of pertussis toxin== | ==Toxic effects of pertussis toxin== | ||
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PERTUSSIS TOXINPERTUSSIS TOXIN
About this StructureAbout this Structure
1prt is a 12 chain structure with sequence from Bordetella pertussis. The September 2005 RCSB PDB Molecule of the Month feature on Cholera Toxin by David S. Goodsell is 10.2210/rcsb_pdb/mom_2005_9. Full crystallographic information is available from OCA.
IntroductionIntroduction
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Binding of PTX to its cellular targetsBinding of PTX to its cellular targets
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Toxin entry and trafficking in target cellsToxin entry and trafficking in target cells
Mechanism of pertussis toxinMechanism of pertussis toxin
Pertussis toxin (PTX) acts on target cells through its A protomer which contains the enzymatically active S1 subunit.
This subunit catalyzes ADP-ribosylation of the α-subunit of trimeric G proteins, which disturbs functions of the target cells and therefore lead to various biological effects.
In facts, substrates of PTX are regulators of the membrane-bound adenylate cyclase. These G proteins bind GTP in order to transduce signals in the cell. When ADP-ribosylation by PTX occurs, the downregulation of the adenylate cyclase activity is inhibited. This inhibition leads to increase cAMP levels in cells, which explains the amount of biological activities of the toxin.
-> picture of the active site of the S1 subunit
labeled in green : key residues surrounding the NAD-binding cavity (Arg9, Trp26, Cys41)
labeled in blue : catalytic residues (His35, Glu129)
The ADP-ribosylation of trimeric G proteins occurs on a cysteine residue in the C-terminal part of the α-subunit.
For that, the donor substrate used by PTX is NAD+, which binds the toxin through Trp26, Arg9 and Cys41 located in the active site of S1.
Concerning the acceptor substrate, it binds to the toxin through residues 180-219 in the C-terminal region of S1. These residues show indeed a high affinity for the G protein and are involved in the catalysis of the ADP-ribosylation.
In the S1 subunit, the catalytic residues His35 and Glu129 have been identified : His35 is involved in the ionization of the nucleophilic thiol of the cysteine residue in the G protein via its ε-N and the carboxylate group of the Glu129 side chain is in contact with the 2'-ribo-hydroxyl of the NAD+.
Toxic effects of pertussis toxinToxic effects of pertussis toxin
See AlsoSee Also
ReferenceReference
- ↑ Locht C, Coutte L, Mielcarek N. The ins and outs of pertussis toxin. FEBS J. 2011 Dec;278(23):4668-82. doi: 10.1111/j.1742-4658.2011.08237.x. Epub, 2011 Aug 4. PMID:21740523 doi:http://dx.doi.org/10.1111/j.1742-4658.2011.08237.x