Structure-Function Relationships of Cytotoxic Proteins One goal is to understand the mechanism by which tumor necrosis factors (TNF-alpha and TNF-beta) elicit a variety of cell-type specific effects. Our discovery that these cytokines exhibit ion channel activity has sparked an intensive investigation of the biological relevance and the role of receptors I and II. Work has begun to unravel the structure of membrane-embedded TNF and to define the ion channel region. Receptor binding poises the trimer protein directly above the membrane in the proper orientation for insection and channel formation. Knowledge gained will enable the manipulation of proteins in such a way as to decrease harmful and often lethal side effects (e.g., cachexia, septic shock, acute respiratory distress) and enhance beneficial properties (e.g., antitumor activities). Our discovery that diphtheria toxin (DTx) has DNase activity has led to a search for its role in target cell destruction. Currently, we are examining the effects of intracellular expression of wildtype and mutant forms of DTx in normal yeast, in yeast that lack specific DNA repair enzymes, and in yeast that encode a mutant form of elongation factor 2, a second target of DTx attack. We have also cloned and purified several forms of the A domain of DTx, and are attempting to define the precise mechanism by which DNA is bound and cleaved. A thorough understanding of the cytotoxic mechanisms of DTx will be invaluable to the design of targetable cell-type specific heteroconjugates, the so-called "magic bullets".
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