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[[Image:Pertussis_toxin_complex.png|thumb|left|300px|Cartoon representation of the molecular structure of pertussis toxin.]]
[[Image:Pertussis_toxin_complex.png|thumb|left|300px|Cartoon representation of the molecular structure of pertussis toxin.]]
'''Pertussis Toxin (PTX)''' is a toxin produced and secreted by the bacteria ''Bordetella pertussis'', also known as the [http://en.wikipedia.org/wiki/Whooping_cough whooping cough] agent.
'''Pertussis Toxin (PTX)''' is a toxin produced and secreted by the bacteria [http://fr.wikipedia.org/wiki/Bordetella_pertussis ''Bordetella pertussis''], also known as the [http://en.wikipedia.org/wiki/Whooping_cough whooping cough] agent.
It is a complex soluble bacterial [[:wiktionary:holotoxin|Holotoxin]], composed of 5 subuntits (named S1 to S5 according to their decreasing molecular weights), arranged in an A-B structure. The A part contains the enzymatically active <scene name='56/568016/Ptx_s1/1'>S1</scene> subunit, which catalyzes ADP-ribosylation of α subunit of [http://en.wikipedia.org/wiki/G_protein trimeric G proteins], thereby disturbing major metabolic functions of the target cells, leading to a variety of biological activities.
It is a complex soluble bacterial [[:wiktionary:holotoxin|Holotoxin]], composed of 5 subuntits (named S1 to S5 according to their decreasing molecular weights), arranged in an A-B structure. The A part contains the enzymatically active <scene name='56/568016/Ptx_s1/1'>S1</scene> subunit, which catalyzes ADP-ribosylation of α subunit of [http://en.wikipedia.org/wiki/G_protein trimeric G proteins], thereby disturbing major metabolic functions of the target cells, leading to a variety of biological activities.
The <scene name='56/568016/Ptx_b/1'>B oligomer</scene> is composed by <scene name='56/568016/Ptx_s2/2'>1S2</scene>:<scene name='56/568016/Ptx_s3/1'>1S3</scene>:<scene name='56/568016/Ptx_s4/1'>2S4</scene>:<scene name='56/568016/Ptx_s5/1'>1S5</scene> and is responsible for binding of the toxin to target cell receptors and for intracellular traficking.
The <scene name='56/568016/Ptx_b/1'>B oligomer</scene> is composed by <scene name='56/568016/Ptx_s2/2'>1S2</scene>:<scene name='56/568016/Ptx_s3/1'>1S3</scene>:<scene name='56/568016/Ptx_s4/1'>2S4</scene>:<scene name='56/568016/Ptx_s5/1'>1S5</scene> and is responsible for binding of the toxin to target cell receptors and for intracellular traficking.
Line 16: Line 16:
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 />
Line 26: Line 26:
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 />


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 '''Lys103''' 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>.


==Toxin entry and trafficking in target cells==
==Toxin entry and trafficking in target cells==
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 56: 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 91: 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 <ref name="Transit">PMID:9204866</ref>and the carboxylate group of the <scene name='56/568016/Ptx_glu129/1'>Glu129</scene> 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 138: Line 137:
cAMP is primary in many biological processes that's why its accumulation leads to the disruption of cellular metabolism and pathological events, according to infected cells. <br />
cAMP is primary in many biological processes that's why its accumulation leads to the disruption of cellular metabolism and pathological events, according to infected cells. <br />
Thus biological activities of PTX are especially ''histamine sensitization'', ''islet activation'' and ''lymphocytosis''.
Thus biological activities of PTX are especially ''histamine sensitization'', ''islet activation'' and ''lymphocytosis''.
==Structural informations allow to produce efficient vaccine==
Crystal structure provided insight into the pathogenic mechanisms of PTX. Informations about the tertiary structure of the active site is 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">PMID:2190139</ref>.


==See Also==
==See Also==
Line 143: Line 147:


==Reference==
==Reference==
<references/>


<references/>
==Proteopedia Page Contributors and Editors==
 
[[User:Lea Clusan|Lea Clusan]] and [[User:Paul Giroud|Paul Giroud]]

Latest revision as of 18:35, 9 January 2014

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Pertussis Toxin produced and secreted by Bordetella pertussis

Drag the structure with the mouse to rotate
Cartoon representation of the molecular structure of pertussis toxin.

Pertussis Toxin (PTX) is a toxin produced and secreted by the bacteria Bordetella pertussis, also known as the whooping cough agent. It is a complex soluble bacterial Holotoxin, composed of 5 subuntits (named S1 to S5 according to their decreasing molecular weights), arranged in an A-B structure. The A part contains the enzymatically active subunit, which catalyzes ADP-ribosylation of α subunit of trimeric G proteins, thereby disturbing major metabolic functions of the target cells, leading to a variety of biological activities. The is composed by ::: and is responsible for binding of the toxin to target cell receptors and for intracellular traficking. This toxin is a major virulence factor of B. pertussis and is a component of vaccines against whooping cough.

Binding of pertussis toxin to its cellular targetsBinding of pertussis toxin to its cellular targets

After being secreted by the Ptl machinery (a member of the type IV secretion system), PTX can interact with almost all mammalian cells, which explains the variety of biological activities of the toxin.
No specific receptors for PTX have been identified but many cell surface sialoglycoproteins are involved in the binding of PTX [1] , 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 [1].

PTX binds its target cells through the B oligomer : S2 and S3 subunits contains at least two carbohydrate-binding sites [2] . 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].

The B oligomer of PTX is involved in some biological activities of the toxin, independently of the enzyme activity. Thus in S2 and in S3 are important for the mitogenic activity of pertussis toxin on murine T lymphocytes [3] , but not on human T cells [4].

Toxin entry and trafficking in target cellsToxin entry and trafficking in target cells

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 [5] [6]. Electron microscopy studies have shown that PTX enters the cells via coated pits [5]. But for now, PTX does not contain a clearly identified translocation domain in the B moiety.

S1 is able to bind to phospholipids bilayers [7] , 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 [8] [9].

Binding of ATP to PTX [10] destabilizes the S1–B oligomer interactions and results in the release of S1 from the holotoxin [11]. This was proposed to occur in the endoplasmic reticulum, as it contains ATP and disulfide isomerases, that may reduce the intramolecular disulphide bonds of S1, therefore help to release the subunit from the holotoxin [12].

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.

PTX bound to ATP : 1bcp

Drag the structure with the mouse to rotate

Mechanism of pertussis toxinMechanism of pertussis toxin

Pertussis toxin 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 leads to various biological effects.

In facts, substrates of PTX are regulators of the membrane-bound adenylate cyclase. 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 [13].
For that, the donor substrate used by PTX is NAD+, which binds the toxin through [14] [15] , [16] and [17] located in the active site of S1.
Concerning the acceptor substrate, it binds to the toxin through in the C-terminal region of S1 [18]. These residues show indeed a high affinity for the G protein and are involved in the catalysis of the ADP-ribosylation [19].
In the S1 subunit, the catalytic residues [20] [19] and [3] 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 [21]and the carboxylate group of the side chain is in contact with the 2'-ribo-hydroxyl of the NAD+ [22].

Toxic effects of pertussis toxinToxic effects of pertussis toxin

Pertussis toxin (PTX) is especially toxic because of its ADP-ribosylation activity on trimeric G proteins but only the Gα subunits in the Gi/0 family are substrates for the toxin.
The ADP-ribosylation of this subunit leads to the loss of inhibition of adenylate cyclase activity, which drive to an increase of cAMP in target cells.
cAMP is primary in many biological processes that's why its accumulation leads to the disruption of cellular metabolism and pathological events, according to infected cells.
Thus biological activities of PTX are especially histamine sensitization, islet activation and lymphocytosis.

Structural informations allow to produce efficient vaccineStructural informations allow to produce efficient vaccine

Crystal structure provided insight into the pathogenic mechanisms of PTX. Informations about the tertiary structure of the active site is 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 [23].

See AlsoSee Also

ReferenceReference

  1. ↑ 1.0 1.1 Armstrong GD, Howard LA, Peppler MS. Use of glycosyltransferases to restore pertussis toxin receptor activity to asialoagalactofetuin. J Biol Chem. 1988 Jun 25;263(18):8677-84. PMID:2454226 Cite error: Invalid <ref> tag; name "Peppler (1988)" defined multiple times with different content
  2. ↑ Stein PE, Boodhoo A, Armstrong GD, Heerze LD, Cockle SA, Klein MH, Read RJ. Structure of a pertussis toxin-sugar complex as a model for receptor binding. Nat Struct Biol. 1994 Sep;1(9):591-6. PMID:7634099
  3. ↑ 3.0 3.1 Lobet Y, Feron C, Dequesne G, Simoen E, Hauser P, Locht C. Site-specific alterations in the B oligomer that affect receptor-binding activities and mitogenicity of pertussis toxin. J Exp Med. 1993 Jan 1;177(1):79-87. PMID:8418210 Cite error: Invalid <ref> tag; name "Locht93" defined multiple times with different content
  4. ↑ Loosmore S, Zealey G, Cockle S, Boux H, Chong P, Yacoob R, Klein M. Characterization of pertussis toxin analogs containing mutations in B-oligomer subunits. Infect Immun. 1993 Jun;61(6):2316-24. PMID:8500874
  5. ↑ 5.0 5.1 el Baya A, Linnemann R, von Olleschik-Elbheim L, Robenek H, Schmidt MA. Endocytosis and retrograde transport of pertussis toxin to the Golgi complex as a prerequisite for cellular intoxication. Eur J Cell Biol. 1997 May;73(1):40-8. PMID:9174670
  6. ↑ Xu Y, Barbieri JT. Pertussis toxin-mediated ADP-ribosylation of target proteins in Chinese hamster ovary cells involves a vesicle trafficking mechanism. Infect Immun. 1995 Mar;63(3):825-32. PMID:7868253
  7. ↑ el Baya A, Linnemann R, von Olleschik-Elbheim L, Robenek H, Schmidt MA. Endocytosis and retrograde transport of pertussis toxin to the Golgi complex as a prerequisite for cellular intoxication. Eur J Cell Biol. 1997 May;73(1):40-8. PMID:9174670
  8. ↑ Castro MG, McNamara U, Carbonetti NH. Expression, activity and cytotoxicity of pertussis toxin S1 subunit in transfected mammalian cells. Cell Microbiol. 2001 Jan;3(1):45-54. PMID:11207619
  9. ↑ Veithen A, Raze D, Locht C. Intracellular trafficking and membrane translocation of pertussis toxin into host cells. Int J Med Microbiol. 2000 Oct;290(4-5):409-13. PMID:11111919 doi:http://dx.doi.org/10.1016/S1438-4221(00)80053-3
  10. ↑ Hazes B, Boodhoo A, Cockle SA, Read RJ. Crystal structure of the pertussis toxin-ATP complex: a molecular sensor. J Mol Biol. 1996 May 17;258(4):661-71. PMID:8637000 doi:10.1006/jmbi.1996.0277
  11. ↑ Hazes B, Read RJ. Accumulating evidence suggests that several AB-toxins subvert the endoplasmic reticulum-associated protein degradation pathway to enter target cells. Biochemistry. 1997 Sep 16;36(37):11051-4. PMID:9333321 doi:http://dx.doi.org/10.1021/bi971383p
  12. ↑ Moss J, Stanley SJ, Burns DL, Hsia JA, Yost DA, Myers GA, Hewlett EL. Activation by thiol of the latent NAD glycohydrolase and ADP-ribosyltransferase activities of Bordetella pertussis toxin (islet-activating protein). J Biol Chem. 1983 Oct 10;258(19):11879-82. PMID:6311827
  13. ↑ Hsia JA, Tsai SC, Adamik R, Yost DA, Hewlett EL, Moss J. Amino acid-specific ADP-ribosylation. Sensitivity to hydroxylamine of [cysteine(ADP-ribose)]protein and [arginine(ADP-ribose)]protein linkages. J Biol Chem. 1985 Dec 25;260(30):16187-91. PMID:3934172
  14. ↑ Cortina G, Barbieri JT. Role of tryptophan 26 in the NAD glycohydrolase reaction of the S-1 subunit of pertussis toxin. J Biol Chem. 1989 Oct 15;264(29):17322-8. PMID:2551899
  15. ↑ Locht C, Capiau C, Feron C. Identification of amino acid residues essential for the enzymatic activities of pertussis toxin. Proc Natl Acad Sci U S A. 1989 May;86(9):3075-9. PMID:2470088
  16. ↑ Burnette WN, Cieplak W, Mar VL, Kaljot KT, Sato H, Keith JM. Pertussis toxin S1 mutant with reduced enzyme activity and a conserved protective epitope. Science. 1988 Oct 7;242(4875):72-4. PMID:2459776
  17. ↑ Locht C, Lobet Y, Feron C, Cieplak W, Keith JM. The role of cysteine 41 in the enzymatic activities of the pertussis toxin S1 subunit as investigated by site-directed mutagenesis. J Biol Chem. 1990 Mar 15;265(8):4552-9. PMID:2155232
  18. ↑ Cortina G, Krueger KM, Barbieri JT. The carboxyl terminus of the S1 subunit of pertussis toxin confers high affinity binding to transducin. J Biol Chem. 1991 Dec 15;266(35):23810-4. PMID:1748655
  19. ↑ 19.0 19.1 Xu Y, Barbancon-Finck V, Barbieri JT. Role of histidine 35 of the S1 subunit of pertussis toxin in the ADP-ribosylation of transducin. J Biol Chem. 1994 Apr 1;269(13):9993-9. PMID:8144593
  20. ↑ Antoine R, Locht C. The NAD-glycohydrolase activity of the pertussis toxin S1 subunit. Involvement of the catalytic HIS-35 residue. J Biol Chem. 1994 Mar 4;269(9):6450-7. PMID:8119996
  21. ↑ Scheuring J, Schramm VL. Pertussis toxin: transition state analysis for ADP-ribosylation of G-protein peptide alphai3C20. Biochemistry. 1997 Jul 8;36(27):8215-23. PMID:9204866 doi:http://dx.doi.org/10.1021/bi970379a
  22. ↑ Locht C, Antoine R. A proposed mechanism of ADP-ribosylation catalyzed by the pertussis toxin S1 subunit. Biochimie. 1995;77(5):333-40. PMID:8527486
  23. ↑ Edwards KM, Karzon DT. Pertussis vaccines. Pediatr Clin North Am. 1990 Jun;37(3):549-66. PMID:2190139

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