Tumor cells or virally infected cells are a danger to our lifes, but fortunately killer cells of the immune defense system which are armed with different specialized digestive enzymes, called granzymes, eradicate these cells in many instances. The granzymes A and B, two of these proteases, are highly efficient triggers of intracellular cell death inducing (cytotoxic) cascades. The same beneficial effector molecules, however, can also turn their powerful energies against transplanted organs, grafted stem cells and self-tissues in autoimmune disorders and are then detrimental and life-theatening to the patients. Among the 120 different serine proteases of the human genome, granzyme A is a unique double-headed protease (homodimer) with two identical catalytic domains connected by a covalent disulfide bond. Clara Hink-Schauer, Eva Estebanez-Perpina, Florian Kurschus, Wolfram Bode and Dieter E. Jenne from the Max-Planck-Institutes of Biochemistry and Neurobiology, Martinsried near Munich, Germany, have now uncovered the secret of this tandem configuration by analyzing the three-dimensional structure of granzyme A at 2.5 resolution (Nature Structural Biology 10, 535-540, July 2003).

Granzyme B specifically recognizes a highly restricted number of flexible surface loops next to the negatively charged amino acid residue called aspartate (Asp) found in a group of intracellular cysteine proteases known as caspases (cysteine protease with aspartate specificity) and activates this proteolytic starter (to be taken unliterally) of the cell death machinery. By contrast, the target sequences that are cleaved by granzyme A after a basic amino acid residue are highly heterogenous and are predominantly found in protein complexes containing subunits with long acidic tails. The so-called SET complex (containing the SET component) is cleaved at multiple s
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Contact: Dr. Dieter Jenne
djenne@neuro.mpg.de
49-898-578-3588
Max-Planck-Gesellschaft
4-Jul-2003