Sandbox Reserved 818: Difference between revisions

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No specific receptors for PTX have been identified but many cell surface [http://en.wikipedia.org/wiki/Sialoglycoprotein '''sialoglycoproteins'''] are involved in the binding of PTX
No specific receptors for PTX have been identified but many cell surface [http://en.wikipedia.org/wiki/Sialoglycoprotein '''sialoglycoproteins'''] are involved in the binding of PTX
<ref name="Peppler (1988)">
<ref name="Peppler (1988)">
Armstrong,G. D.,Howard,L. A. & M S Peppler (1988) Use of glycosyltransferases to restore pertussis toxin receptor activity to asialoagalactofetuin. J. Biol. Chem., 263: 8677-8684.
PMID:2454226
</ref>
</ref>
, together with '''glycoproteins''': sugar moieties allow the recognition of the toxin and the carbohydrate sequence '''NeuAcα(2,6)-Galβ4GlcNAc''' is particularly important however sugar sequence alone is not sufficient
, together with '''glycoproteins''': sugar moieties allow the recognition of the toxin and the carbohydrate sequence '''NeuAcα(2,6)-Galβ4GlcNAc''' is particularly important however sugar sequence alone is not sufficient
<ref name="Peppler (1988)">
<ref name="Peppler (1988)">
Brennan, M. J., David, J. L., Kenimer, J. G., & Manclark, C. R. (1988). Lectin-like binding of pertussis toxin to a 165-kilodalton Chinese hamster ovary cell glycoprotein. Journal of Biological Chemistry, 263(10), 4895-4899.
PMID:3350815
</ref>.
</ref>.
<br />
<br />
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PTX binds its target cells through the ''B oligomer'' : ''S2'' and ''S3'' subunits contains at least two '''carbohydrate-binding sites'''
PTX binds its target cells through the ''B oligomer'' : ''S2'' and ''S3'' subunits contains at least two '''carbohydrate-binding sites'''
<ref name="Read (1994)">
<ref name="Read (1994)">
Stein, P. E., Boodhoo, A., Armstrong, G. D., Heerze, L. D., Cockle, S. A., Klein, M. H., & Read, R. J. (1994). Structure of a pertussis toxin–sugar complex as a model for receptor binding. Nature Structural & Molecular Biology, 1(9), 591-596.
PMID:7634099
</ref>
</ref>
. 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 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 />
Line 32: Line 32:
The B oligomer of PTX is involved in some biological activities of the toxin, independently of the enzyme activity. Thus <scene name='56/568016/Ptx_asn105/1'>Asn105</scene> in ''S2'' and <scene name='56/568016/Ptx_lys105/1'>Lys105</scene> in ''S3'' are important for the mitogenic activity of pertussis toxin on murine T lymphocytes  
The B oligomer of PTX is involved in some biological activities of the toxin, independently of the enzyme activity. Thus <scene name='56/568016/Ptx_asn105/1'>Asn105</scene> in ''S2'' and <scene name='56/568016/Ptx_lys105/1'>Lys105</scene> in ''S3'' are important for the mitogenic activity of pertussis toxin on murine T lymphocytes  
<ref name="Locht93">
<ref name="Locht93">
Lobet, Y., Feron, C., Dequesne, G., Simoen, E., Hauser, P., & Locht, C. (1993). Site-specific alterations in the B oligomer that affect receptor-binding activities and mitogenicity of pertussis toxin. The Journal of experimental medicine, 177(1), 79-87.
PMID:8418210
</ref>
</ref>
, but not on human T cells  
, but not on human T cells  
<ref name="Klein93">
<ref name="Klein93">
Loosmore, S., Zealey, G., Cockle, S., Boux, H., Chong, P. E. L. E., Yacoob, R., & Klein, M. (1993). Characterization of pertussis toxin analogs containing mutations in B-oligomer subunits. Infection and immunity, 61(6), 2316-2324.
PMID:8500874
</ref>.
</ref>.


Line 42: Line 42:
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  
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 name="Schmidt MA (1997)">
<ref name="Schmidt MA (1997)">
El Baya, A., Linnemann, R., von Olleschik-Elbheim, L., Robenek, H., & Schmidt, M. A. (1997). Endocytosis and retrograde transport of pertussis toxin to the Golgi complex as a prerequisite for cellular intoxication. European journal of cell biology, 73(1), 40.
PMID:9174670
</ref>
</ref>
<ref name="Xu95">
<ref name="Xu95">
Xu, Y., & Barbieri, J. T. (1995). Pertussis toxin-mediated ADP-ribosylation of target proteins in Chinese hamster ovary cells involves a vesicle trafficking mechanism. Infection and immunity, 63(3), 825-832.
PMID:7868253
</ref>.
</ref>.
Electron microscopy studies have shown that PTX enters the cells via ''coated pits''  
Electron microscopy studies have shown that PTX enters the cells via ''coated pits''  
<ref name="Schmidt MA (1997)">
<ref name="Schmidt MA (1997)">
El Baya, A., Linnemann, R., von Olleschik-Elbheim, L., Robenek, H., & Schmidt, M. A. (1997). Endocytosis and retrograde transport of pertussis toxin to the Golgi complex as a prerequisite for cellular intoxication. European journal of cell biology, 73(1), 40.
PMID:9174670
</ref>.
</ref>.
But for now, PTX does not contain a clearly identified translocation domain in the B moiety.
But for now, PTX does not contain a clearly identified translocation domain in the B moiety.
Line 55: Line 55:
S1 is able to bind to phospholipids bilayers
S1 is able to bind to phospholipids bilayers
<ref name="Carbonetti08">
<ref name="Carbonetti08">
Plaut, R. D., & Carbonetti, N. H. (2008). Retrograde transport of pertussis toxin in the mammalian cell. Cellular microbiology, 10(5), 1130-1139.
PMID:9174670
</ref>
</ref>
, 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  
, 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  
<ref name="Carbonetti01">
<ref name="Carbonetti01">
Castro, M. G., McNamara, U., & Carbonetti, N. H. (2001). Expression, activity and cytotoxicity of pertussis toxin S1 subunit in transfected mammalian cells. Cellular microbiology, 3(1), 45-54.
PMID:11207619
</ref>
</ref>
<ref name="Locht00">
<ref name="Locht00">
Veithen, A., Raze, D., & Locht, C. (2000). Intracellular trafficking and membrane translocation of pertussis toxin into host cells. International journal of medical microbiology, 290(4), 409-413.
PMID:11111919
</ref>.
</ref>.


Binding of ATP to PTX  
Binding of ATP to PTX  
<ref name="Read96">
<ref name="Read96">
Hazes, B., Boodhoo, A., Cockle, S. A., & Read, R. J. (1996). Crystal structure of the pertussis toxin–ATP Complex: A molecular sensor. Journal of molecular biology, 258(4), 661-671.
PMID:8637000
</ref>
</ref>
destabilizes the S1–B oligomer interactions and results in the release of S1 from the holotoxin
destabilizes the S1–B oligomer interactions and results in the release of S1 from the holotoxin
<ref name="Read97">
<ref name="Read97">
Hazes, B., & Read, R. J. (1997). Accumulating evidence suggests that several AB-toxins subvert the endoplasmic reticulum-associated protein degradation pathway to enter target cells. Biochemistry, 36(37), 11051-11054.
PMID:9333321
</ref>.
</ref>.
This was proposed to occur in the endoplasmic reticulum, as it contains 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
This was proposed to occur in the endoplasmic reticulum, as it contains 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
<ref name="Hewlett83">
<ref name="Hewlett83">
Moss, J., Stanley, S. J., Burns, D. L., Hsia, J. A., Yost, D. A., Myers, G. A., & Hewlett, E. L. (1983). Activation by thiol of the latent NAD glycohydrolase and ADP-ribosyltransferase activities of Bordetella pertussis toxin (islet-activating protein). Journal of Biological Chemistry, 258(19), 11879-11882.
PMID:6311827
</ref>.
</ref>.


Line 90: Line 90:
The ADP-ribosylation of trimeric G proteins occurs on a '''cysteine residue''' in the ''C-terminal part of the α-subunit''
The ADP-ribosylation of trimeric G proteins occurs on a '''cysteine residue''' in the ''C-terminal part of the α-subunit''
<ref name="Moss85">
<ref name="Moss85">
Hsia, J. A., Tsai, S. C., Adamik, R., Yost, D. A., Hewlett, E. L., & Moss, J. (1985). Amino acid-specific ADP-ribosylation. Sensitivity to hydroxylamine of [cysteine (ADP-ribose)] protein and [arginine (ADP-ribose)] protein linkages. Journal of Biological Chemistry, 260(30), 16187-16191.
PMID:3934172
</ref>. <br />
</ref>. <br />
For that, the donor substrate used by PTX is '''NAD<sup>+</sup>''', which binds the toxin through <scene name='56/568016/Ptx_trp26/1'>Trp26</scene>
For that, the donor substrate used by PTX is '''NAD<sup>+</sup>''', which binds the toxin through <scene name='56/568016/Ptx_trp26/1'>Trp26</scene>
<ref name="Barbieri89">
<ref name="Barbieri89">
Cortina, G. & Barbieri, J. T. (1989). Role of tryptophan 26 in the NAD glycohydrolase reaction of the S-1 subunit of pertussis toxin. J. Biol. Chem. 264: 17322-17328.
PMID:2551899
</ref>
</ref>
<ref name="Feron89">
<ref name="Feron89">
Locht, C., Capiau, C., & Feron, C. (1989). Identification of amino acid residues essential for the enzymatic activities of pertussis toxin. Proceedings of the National Academy of Sciences, 86(9), 3075-3079.
PMID:2470088
</ref>
</ref>
, <scene name='56/568016/Ptx_arg9/1'>Arg9</scene>
, <scene name='56/568016/Ptx_arg9/1'>Arg9</scene>
<ref name="Keith88">
<ref name="Keith88">
Burnette, W. N., Cieplak, W. I. T. O. L. D., Mar, V. L., Kaljot, K. T., Sato, H., & Keith, J. M. (1988). Pertussis toxin S1 mutant with reduced enzyme activity and a conserved protective epitope. Science, 242(4875), 72-74.
PMID:2459776
</ref>
</ref>
and <scene name='56/568016/Ptx_s1/2'>Cys41</scene>
and <scene name='56/568016/Ptx_s1/2'>Cys41</scene>
<ref name="Keith90">
<ref name="Keith90">
Locht, C., Lobet, Y., Feron, C., Cieplak, W., & Keith, J. M. (1990). The role of cysteine 41 in the enzymatic activities of the pertussis toxin S1 subunit as investigated by site-directed mutagenesis. Journal of Biological Chemistry, 265(8), 4552-4559.
PMID:2155232
</ref>
</ref>
located in the ''active site of S1''. <br />
located in the ''active site of S1''. <br />
Concerning the acceptor substrate, it binds to the toxin through <scene name='56/568016/Ptx_180_219/1'>residues 180-219</scene> in the ''C-terminal region of S1''  
Concerning the acceptor substrate, it binds to the toxin through <scene name='56/568016/Ptx_180_219/1'>residues 180-219</scene> in the ''C-terminal region of S1''  
<ref name="Barbieri91">
<ref name="Barbieri91">
Cortina, G., Krueger, K. M., & Barbieri, J. T. (1991). The carboxyl terminus of the S1 subunit of pertussis toxin confers high affinity binding to transducin. Journal of Biological Chemistry, 266(35), 23810-23814.
PMID:1748655
</ref>.
</ref>.
These residues show indeed a high affinity for the G protein and are involved in the catalysis of the ADP-ribosylation  
These residues show indeed a high affinity for the G protein and are involved in the catalysis of the ADP-ribosylation  
<ref name="Barbieri94">
<ref name="Barbieri94">
Xu, Y., Barbancon-Finck, V., & Barbieri, J. T. (1994). Role of histidine 35 of the S1 subunit of pertussis toxin in the ADP-ribosylation of transducin. Journal of Biological Chemistry, 269(13), 9993-9999.
PMID:8144593
</ref>. <br />
</ref>. <br />
In the S1 subunit, the ''catalytic residues'' <scene name='56/568016/Ptx_his35/1'>His35</scene>
In the S1 subunit, the ''catalytic residues'' <scene name='56/568016/Ptx_his35/1'>His35</scene>
<ref name="Locht94">
<ref name="Locht94">
Antoine, R., & Locht, C. (1994). The NAD-glycohydrolase activity of the pertussis toxin S1 subunit. Involvement of the catalytic HIS-35 residue. Journal of Biological Chemistry, 269(9), 6450-6457.
PMID:8119996
</ref>
</ref>
<ref name="Barbieri94">
<ref name="Barbieri94">
Xu, Y., Barbancon-Finck, V., & Barbieri, J. T. (1994). Role of histidine 35 of the S1 subunit of pertussis toxin in the ADP-ribosylation of transducin. Journal of Biological Chemistry, 269(13), 9993-9999.
PMID:8144593
</ref>
</ref>
and <scene name='56/568016/Ptx_glu129/1'>Glu129</scene>
and <scene name='56/568016/Ptx_glu129/1'>Glu129</scene>
<ref name="Locht93">
<ref name="Locht93">
Antoine, R., Tallett, A., Van Heyningen, S., & Locht, C. (1993). Evidence for a catalytic role of glutamic acid 129 in the NAD-glycohydrolase activity of the pertussis toxin S1 subunit. Journal of Biological Chemistry, 268(32), 24149-24155.
PMID:7901213
</ref>
</ref>
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 [99] and the carboxylate group of the Glu129 side chain is in contact with the 2'-ribo-hydroxyl of the NAD<sup>+</sup>  
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 [99] and the carboxylate group of the Glu129 side chain is in contact with the 2'-ribo-hydroxyl of the NAD<sup>+</sup>  
<ref name="Antoine95">
<ref name="Antoine95">
Locht, C., & Antoine, R. (1995). A proposed mechanism of ADP-ribosylation catalyzed by the pertussis toxin S1 subunit. Biochimie, 77(5), 333-340.
PMID:8527486
</ref>.
</ref>.


Line 141: Line 141:
Cristal structure provided insight into the pathogenic mechanisms of PTX. Informations about the tertiary structure of the active site a good basis for elimination of the catalytic activity in recombinant molecules for vaccine use.
Cristal structure provided insight into the pathogenic mechanisms of PTX. Informations about the tertiary structure of the active site a good basis for elimination of the catalytic activity in recombinant molecules for vaccine use.


For example, one highly detoxified PTX analog contains two alterations in the S1 subunit (Arg9 to Lys; Glu129 to Gly), each of which is able to totally abolish the enzymativ activity of the toxin. This molecule already belongs to the new-generation of pertussis vaccines <ref name="Karzon90">
For example, one highly detoxified PTX analog contains two alterations in the S1 subunit (Arg9 to Lys; Glu129 to Gly), each of which is able to totally abolish the enzymativ activity of the toxin. This molecule already belongs to the new-generation of pertussis vaccines <ref name="Karzon90">PMID:2190139</ref>.
Edwards, K. M., & Karzon, D. T. (1990). Pertussis vaccines. Pediatric clinics of North America, 37(3), 549.
</ref>.




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