Pieter Roelfsema

With this motivation, the groups of Michael Groll at the Technical University of Munich and of Marcus Groettrup at the University of Konstanz have recently solved the crystal structures of both the constitutive proteasome and the immunoproteasome of mice, each with and without the epoxyketone PR957, which is the only selective inhibitor of b5i known so far. In addition, the researchers also solved the structure of the yeast proteasome with and without this inhibitor (Cell (2012), 148, 727–738). The detailed analysis of these structures revealed the molecular basis for the specificity of the inhibitor, which turned out to be extremely subtle. The researchers found that a single methionine residue in the immunoproteasome adopts a different conformation than in the constitutive proteasome due to small structural differences in its surroundings. “This distinct conformation is crucial,” explains the first author of the paper, Eva Maria Huber. “It results in a larger pocket in the immunoproteasome, which therefore preferentially accommodates bulky amino acids and also the inhibitor. In contrast, constitutive proteasomes harbor a significantly smaller cavity that hampers binding of PR-957.” What does all this mean for disease and drug development? “How the immunoproteasome is mechanistically involved in the pathogenesis of autoimmune diseases is still elusive,” says Marcus Groettrup. “The proteasome can perform site-specific cleavages within proteins and release a processed, biologically active polypeptide. We hypothesize that the immunoproteasome may selectively process or degrade a factor which is required for proinflammatory immune responses in autoimmunity.” As yet, only one approved pharmaceutical agent, the cancer drug bortezomib, targets the proteasome, but the authors hope that, on the basis of the detailed structural knowledge they have provided for the whole range of different subunits in the constitutive proteasome and in the immunoproteasome, more specific drugs can be developed to target specific functions of the proteasome. Thus, understanding the complexities of oligomeric proteins will also become very useful knowledge.