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A TWO-LANE ROAD TO RUIN
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 Å resolution. Granzyme B specifically recognizes a highly restricted number of flexible surface loops next to the negatively charged amino acid residue called aspartate 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 sites and dismantled during killer cell attack. A cellular Mg2+-dependent DNase, called NM23-H1, is thereby freed from this complex and degrades the DNA nucleus by cutting the strands of the DNA double helix at numerous sites. The research team of the Max-Planck-Society in Martinsried now explains how the two identical molecules are assembled into a doubled-headed protease for the defense. The two catalytic centers point in exactly opposite directions. Both surfaces on the front and backside of the dimer are functionally equivalent. Each molecule (subunit) thus fulfills a concurrent dual function, presenting substrates with their back to the adjacent partner and cleaving substrates with their catalytically active front side. Moreover, the scientists presented an elegant low budget solution to produce this dimeric enzyme first as a stable dimeric progranzyme and second as a double-active mature protease at in large quantities. Granzymes are obvious therapeutic targets for preventing killer cell-mediated cell damage with cell-penetrating inhibitors. Easy access to large quantities of this enzyme and its three-dimensional structure are important prerequisites for the rapid development and rational improvement of existing serine protease inhibitors. Inhibitors that save host cells from the attack by natural killer cells and cytotoxic T cells could gain great significance as practical therapeutics in graft-versus-host diseases, chronic viral infections, and autoimmune disorders like rheumatoid arthritis and multiple sclerosis. http://www.mpg.de/portal/index.html
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