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Periodic Report Summary 1 - PROTEAMICS (Three dimentional architectures of dynamic interactions of 26S proteasome)

In eukaryotic cells, the 26S proteasome is responsible for the regulated degradation of intracellular proteins. The 26S proteasome is an ATP-dependent protease comprising two sub-complexes: 20S Core Particle (CP) and 19S Regulatory Particles (RP). Besides 33 canonical subunits, the 26S proteasome also often comprises several proteasome interacting proteins (PIPs) that interact transiently with the 26S proteasome, including deubiquitylating enzymes, ubiquitin receptors, as well as chaperones required for assembly (Finley 2009, Sakata, Stengel et al. 2011). Proteasome activity itself is also regulated by PIP binding, and we have addressed the structural basis of such regulation using electron microscopy. We have succeeded to form a stable complex of the 26S proteasome with Ubp6 by adding its catalytic inhibitor, ubiquitin aldehyde (UbAld). The deubiquitylating enzyme Ubp6 functions as a timing device to control the duration of substrate degradation by trimming its polyubiquitin chain. In addition, binding of UbAld to Ubp6 enhances the catalytic activity of the 20S CP. Our recent study revealed the localisation of Ubp6 on the 26S proteasome and addressed the conformational changes of the proteasome induced by Ubp6 binding. The catalytic domain of Ubp6 is located in close vicinity of Rpt1. Ubp6 modulates the conformational landscape of the proteasome, favouring an intermediate state between the resting and the substrate processing conformations. This is the first study showing the structural basis of the regulatory role of a PIP (Aufderheide, Beck et al. 2015). Thus, the PIPs regulate the proteasome function by not only providing an additional function but also by altering the conformation of the proteasome.
Recently, we reported a high resolution structure of human proteasome at a resolution of 3.9 Å (Schweitzer et al., 2016). The structure allowed us to make a precise atomic model and provided mechanical insights into the proteasome function. Strikingly, all six ATPase subunits coordinate nucleotides in the ATP binding pockets. Among these nucleotides only Rpt6 incorporates ADP, whereas the rest of subunits binds ATPs. Further structural and biophysical studies will help us to understand how the proteasome utilizes ATP hydrolysis to translocate substrates (Wehmer et al., 2016).

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Life Sciences
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