Abstract
The mature form of diphtheria toxin (535 amino acid protein) is selectively cleaved by trypsin into two polypeptides. The N-terminal 192 amino acid polypeptide, fragment A, has been shown to carry the catalytic center for ADP-ribosylation of eukaryotic elongation factor 2 (EF-2). Fragment B of diphtheria toxin, a 343 amino acid polypeptide, contains the lipid associating regions that facilitate the membrane translocation of fragment A into the cytosol of sensitive cells, as well as the diphtheria toxin receptor binding domain (1). Murphy et al. (2) have recently shown that the C-terminal 50 amino acids of the toxin molecule are required for the formation of the receptor binding domain. The process by which diphtheria toxin intoxicates sensitive eukaryotic cells involves at least the following steps: (i) the binding of diphtheria toxin to the cell surface receptor (3), (ii) internalization of toxin by receptor mediated endocytosis (4), and upon acidification of the endosome, (iii) a partial unfolding of fragment B, thereby exposing the lipid associating regions of toxin (5, 6), and facilitating (iv) the membrane translocation of fragment A to the cytosol. Yamiazumi et al. (7) have elegantly demonstrated that the introduction of a single molecule of fragment A into the cytosol is sufficient to be lethal for that cell.
Published Version
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