FUSION PROTEINS WITH TOXIC ACTIVITY - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 247

TABLE 17.1 Natural Receptors and Enzymatic Activity of Toxins

Toxin Receptor Enzymatic Activity Cellular Target

Diphtheria toxin Heparin binding epidermal growth factor precursor ADP-ribosyl transferase Elongation factor 2

Pseudomonas exotoxin A Low-density lipoprotein receptor-related protein 1 ADP-ribosyl transferase Elongation factor 2

Antrax protective antigen
Antrax endema factor
Antrax lethal factor

Integrin-like cell surface receptor (TEM8 and CMG2)
None
None

None
Adenlylate cyclase
Zinc endoprotease

None
cAMP modulated proteins
MAPKK

Shiga toxin Glycosphingolipid globotriaosylceramide (Gb3) N-glycosylase 28S rRNA

Botulinum neurotoxin Synaptotagmin (Syt) and synaptic vessel protein (SV2) Zinc endoprotease SNARE proteins

Ricin Galactose or N-acetylgalactosamine residues N-glycosylase 28S rRNA

Gelonin, bouganin None N-glycosylase 28S rRNA

FIGURE 17.2 Mechanism of some frequently used bacterial toxins. (A) After binding to its
receptor (R) and cleavage, Diphtheria toxin is internalized. The reduction of the remaining disulfide
bond separates the binding domain (B) from the catalytic (A) and translocation (T) domain. A pH
induced conformational change enables the transfer of A and T to the cytosol, where A blocks the
elongation factor 2 (EF2). (B) The C-terminal lysine (K) of Pseudomonas exotoxin is cleaved off by a
serum peptidase before internalization through coated pits. Reduction of its disulfide bridge and furin
cleavage separates binding domain (Ia) from the catalytic domain (III) that is still bound to the
translocation domain (II). In the Golgi apparatus, the exposed REDL sequence is captured by the
KDEL receptor and the toxin is shuttled to the endoplasmic reticulum (ER). There the translocation
domain mediates the escape to the cytosol where it inactivates EF2. (C) The PA domain of the anthrax
toxin binds to its receptor and is truncated by furin. PA assembles into homo-heptamer that associates
with three molecules of LF and/or EF. The lowering of the pH in the endosome leads to a
conformational change of the pore-like PA structure into a real pore through which LF and/or
EF translocate to the cytoplasm, where LF degrades MEK kinases while EF increases cAMP
concentration.