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From the
1 From the Department of Bacteriology, University of California, Los Angeles, California 90024
The activity of diphtheria toxin in catalyzing transfer of the adenosine diphosphate ribose moiety of NAD+ into covalent linkage with the mammalian peptidyl transfer RNA translocation factor, transferase II, is dependent upon exposure of the toxin to thiols. The toxin is almost completely inactive when assayed in the absence of thiols, but may be maximally activated by treatment with 50 mm dithiothreitol for 10 min. The activation process has been correlated with certain structural features of the toxin. Studies involving electrophoresis on polyacrylamide gels in the presence of sodium dodecyl sulfate have led us to conclude that toxin consists of a mixture of two similar proteins of molecular weight about 63,000. One consists of intact, 63,000-dalton polypeptide chains (intact toxin), while the other (nicked toxin) consists of two fragments of 24,000 and 39,000 daltons (A and B, respectively) linked by at least one disulfide bridge. Treatment of toxin with thiols results in dissociation of the latter into Fragments A and B. Fragment A is enzymically active, and probably accounts for all the activity of thiol-treated toxin. Fragment B is almost certainly devoid of activity for reasons which are discussed, although this has not been demonstrated experimentally. Intact toxin appears to be inactive before or after treatment with dithiothreitol. In the accompanying paper we show that intact toxin is a precursor of nicked toxin, and may be converted into the latter by treatment with trypsin.
Structure and Activity of Diphtheria Toxin
I. THIOL-DEPENDENT DISSOCIATION OF A FRACTION OF TOXIN INTO ENZYMICALLY ACTIVE AND INACTIVE FRAGMENTS
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