1.C.72 The Pertussis Toxin (PTX) Family

Pertussis toxin is an NAD-dependent ADP-ribosyltransferase. It catalyzes the ADP-ribosylation of a cysteine in the alpha subunit of heterotrimeric G proteins. In the absence of G proteins it also catalyzes the cleavage of NAD(+) into ADP-ribose and nicotinamide. It irreversibly uncouples the G-alpha GTP-binding proteins from their membrane receptors.

Pertussis toxin contains five different chains, S1-S5. They are organized into 2 functional subunits: A, composed of S1 (which is toxic) and B, containing S2, S3, S5, and two copies of S4 (B binds to the membrane receptors). Dimers of S2-S4 and S3-S4 are held together by S5. The x-ray structure has been solved to 2.9 Å resolution (Hazes et al., 1996; Stein et al., 1994).

Pertussis toxin subunits require the Sec-dependent general secretory pathway (TC #3.A.5) for export across the cytoplasmic membrane to the periplasm. The type IV secretion pathway (IVSP) system (TC #3.A.7) then exports it across the outer membrane. Finally, unlike most other IVSP substrates, the holotoxin autotranslocates itself across the host cytoplasmic membrane into the host cell (Gauthier et al., 2003). Thus it must form a channel. Complex B (S2S3(S4)2S5) binds the glycan receptors on the host cell surface and facilitates translocation of the toxic subunit (S1) across the membrane (Beddoe et al., 2010). Subunits S2 and S3 are related and may be distantly related to members of the Aerolysin Family (TC #1.C.4).

A homologue, ArtAB of Salmonella enterica (TC#1.C.72.2.1), shows sequence similarity with pertussis toxin A, but ArtB shows little similarity with the S2-55 subunits of pertussis toxin. It shows no conserved domains in the CDD. However, homologues of ArtB are found in many Salmonella strains including Typhi, and Paratyphi, in Yersinia pestis and Y. enterocolitica, in the subtilase cytotoxin of E. coli (TC# 1.C.72.3.1) and in hypothetical proteins of Bordetella species including B. pertussis.


 

References:

Beddoe, T., A.W. Paton, J. Le Nours, J. Rossjohn, and J.C. Paton. (2010). Structure, biological functions and applications of the AB5 toxins. Trends. Biochem. Sci. 35: 411-418.

Cherry, J.D. (2007). Historical Perspective on Pertussis and Use of Vaccines to Prevent It. Microbe 2: 139-144.

Gauthier, A., N.A. Thomas, and B.B. Finlay. (2003). Bacterial injection machines. J. Biol. Chem. 278: 25273-25276.

Hazes, B., A. Boodhoo, S.A. Cockle, and R.J. Read. (1996). Crystal structure of the pertussis toxin-ATP complex: a molecular sensor. J. Mol. Biol. 258: 661-671.

Liu, D., H. Guo, W. Zheng, N. Zhang, T. Wang, P. Wang, and X. Ma. (2016). Discovery of the cell-penetrating function of A2 domain derived from LTA subunit of Escherichia coli heat-labile enterotoxin. Appl. Microbiol. Biotechnol. 100: 5079-5088.

Paton A.W., T. Beddoe, C.M. Thorpe, J.C. Whisstock, M.C. Wilce, J. Rossjohn, U.M. Talbot, J.C. Paton. (2006). AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature. 443: 548-552.

Saitoh M., K. Tanaka1, K. Nishimori1, S. Makino, T. Kanno1, R. Ishihara1, S. Hatama1, R. Kitano, M. Kishima, T. Sameshima, M. Akiba, M. Nakazawa, Y. Yokomizo and I. Uchida1. (2005). The artAB genes encode a putative ADP-ribosyltransferase toxin homologue associated with Salmonella enterica serovar Typhimurium DT104. Microbio. 151: 3089-3096

Stein, P.E., A. Boodhoo, G.D. Armstrong, S.A. Cockle, M.H. Klein, and R.J. Read. (1994). The crystal structure of pertussis toxin. Structure 2: 45-57.

Wehrum, S., L. Siukstaite, D.J. Williamson, T.R. Branson, T. Sych, J. Madl, G.C. Wildsmith, W. Dai, E. Kempmann, J.F. Ross, M. Thomsen, M.E. Webb, W. Römer, and W.B. Turnbull. (2022). Membrane Fusion Mediated by Non-covalent Binding of Re-engineered Cholera Toxin Assemblies to Glycolipids. ACS Synth Biol. [Epub: Ahead of Print]

Examples:

TC#NameOrganismal TypeExample
1.C.72.1.1Pertussis toxinBacteriaPertussis toxin of Bordetella pertussis A (S1) + B (S2-S5)
Subunit S1 (P04977)
Subunit S2 (P04978)
Subunit S3 (P04979)
Subunit S4 (P0A3R5)
Subunit S5 (P04981)
 
Examples:

TC#NameOrganismal TypeExample
1.C.72.2.1The ADP-ribosyltransferase toxin, ArtAB (Saitoh et al., 2005) (ArtA but not ArtB is demonsratively homologous to subunits in pertussis toxin)BacteriaArtAB of Salmonella enterica serovar Typhimurium
ArtA (Q404H4)
ArbB (Q404H3)
 
Examples:

TC#NameOrganismal TypeExample
1.C.72.3.1

The Subtilase cytotoxin, SubAB. Pentameric SubB, but not SubA, is homologous to ArtB of Salmonella enterica. SubA (AB5 subtilase) cytotoxin inactivates the endoplasmic reticulum chaperone, BiP (Paton et al., 2006; Beddoe et al., 2010).

Bacteria

Subtilase cytotoxin AB (SubAB) of E. coli
Subtilase A (Q3ZTX7)
Subtilase B (Q3ZTX8)

 
Examples:

TC#NameOrganismal TypeExample
1.C.72.4.1

Heat labile enterotoxin AB, EltAB, ItpAB, ToxAB, LT-AB, cholera toxin (258 aas and 124 aas, respectively). The biological activity of the toxin is produced by the A chain, which activates intracellular adenyl cyclase. The A2 domain of LTA has cell penitration function (Liu et al. 2016). LT holotoxin can enter intestinal epithelial cells and cause diarrhea. The A2 domain might be useful as a transport vehicle for other proteins (Liu et al. 2016). A biotinylated cholera toxin becomes a fusogenic lectin upon cross-linking with streptavidin. This reengineered protein brings about hemifusion and fusion of vesicles as demonstrated by mixing of fluorescently labeled lipids between vesicles as well as content mixing of liposomes filled with fluorescently labeled dextran (Wehrum et al. 2022).

EltAB of E. coli 078:H11

 
1.C.72.4.2

Heat labile enterotoxin IIB, A (α)-chain of 685 aas/B chain of

Enterotoxin of Leptospira borgpetersenii