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{{STRUCTURE_1prt|  PDB=1prt |  SCENE= }}

 

 

 

[[1prt]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Bordetella_pertussis Bordetella pertussis]. The September 2005 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Cholera Toxin''  by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2005_9 10.2210/rcsb_pdb/mom_2005_9]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PRT OCA].

 

 

==Introduction==

Adding an introduction <br />

3-7 sentences about what the protein or topic is and why it is important <br />

first sentence should contain the name of the topic and it should be an interwiki link (so on the Hemoglobin page, you might start by writing "[[Hemoglobin]] is the protein...") <br />

touch on medical relevance if there is any <br />

After being secreted, pertussis toxin (PTX) can interact with almost all mammalian cells, which explains the variety of biological activities of the toxin. <br />

No specific receptors for PTX have been identified but many cell surface '''sialoglycoproteins''' are involved in the binding of PTX [64], together with '''glycoproteins''': sugar moieties allow the recognition of the toxin and the carbohydrate sequence '''NeuAcα(2,6)-Galβ4GlcNAc''' is particularly important but sugar sequence alone is not sufficient [69]. <br />

PTX binds its target cells through the ''B oligomer'' : ''S2'' and ''S3'' subunits contains at least two '''carbohydrate-binding sites''' [70]. The N-terminal regions of these subunits are involved in receptor binding and the C-terminal domains of S2 and S3 adopt a fold found in other carbohydrate-binding proteins [73]. <br />

The B oligomer of PTX is involved in some biological activities of the toxin, independently of the enzyme activity. Thus '''Asn105''' in ''S2'' and '''Lys103''' in ''S3'' are important for the mitogenic activity of pertussis toxin on murine T lymphocytes [71], but not on human T cells [74].

 

After binding to the target cell receptors, PTX enters the cells via receptor mediated endocytosis, and then follows the retrograde transport system, involving both the Golgi apparatus and the endoplasmic reticulum  

</ref>.[75,76].

 

Electron microscopy studies have shown that PTX enters the cells via coated pits  

S1 is able to bind to phospholipids bilayers [78], suggesting that it may directly interact with the target cell membranes and mediate its translocation, and also that the B oligomer is not essential for this step. Results obtained from cell transfection experiments support this hypothesis [80,81].

Binding of ATP to PTX [82] destabilizes the S1–B oligomer interactions and results in the release of S1 from the holotoxin [83]. This was proposed to occur in the endoplasmic reticulum, as it contain ATP and [http://en.wikipedia.org/wiki/Protein_disulfide-isomerase disulfide isomerases], that may reduce the intramolecular disulphide bonds of S1, therefore help to release the subunit from the holotoxin [85,86].

These observations imply that the holotoxin traffics via the endosomal pathway and Golgi apparatus to the endoplasmic reticulum, where it meet ATP and disulphide isomerase, leading to the release of the S1 subunit. S1 then translocate directly through the endoplasmic reticulum membrane into the cytosol (Fig ?)

Pertussis toxin (PTX) acts on target cells through its A protomer which contains the '''enzymatically active S1 subunit'''. <br />

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.

 

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⁺''', 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. <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⁺.

<ref group="xtra">PMID:008075982</ref><references group="xtra"/>

<ref group="xtra">PMID:21740523</ref><references group="xtra"/>