Reduce – Reuse – Recycle Insights into the Cellular Protein Recycling Machine by Integrative Modeling
(sign-up)Dr. Till Rudack
|Time:||1:30 p.m. - 2:30 p.m.|
Beckman Room 3269
|Event Contact:||Donna H Fackler
Theoretical and Computational Biophysics Group
Protein recycling is a key process crucial to a wide spectrum of regulatory processes within living cells. The executive player in this process is an ATP hydrolysis driven molecular machine called 26S proteasome, that recruits, unfolds, and degrades poly-ubiquitin tagged proteins through a complex interaction clockwork of 33 different protein subunits. Given its critical role, the proteasome is involved in multiple human diseases, and it serves as a perfect target for a plethora of different drugs, most prominently, those commonly used in chemotherapy of cancer. Despite its substantial role in the cell’s life cycle, the proteasome is one of the last key molecular machines, which detailed atomic mechanism still remains elusive.
Driven by the revolutionary advance of electron microscopy we developed an integrative modeling approach to derive structural models from 3 to 12 Å resolution cryo-EM densities. Our approach combines molecular dynamics flexible fitting (MDFF) with de novo structure prediction algorithms in an interactive way allowing for incorporation of user expertise into model building. This approach is in particular beneficial as presently it is highly challenging to employ crystallographic modeling software to obtain models for cryo-EM densities with a resolution of ~4 Å.
Employing this approach we obtained in collaboration with the Baumeister department (MPI for Biochemistry) the first atomic structure of the human 26S proteasome with bound nucleotides (Schweitzer et al. PNAS 2016) based on a 3.9 Å resolution cryo-EM density. In a follow up study, we derived four more structural models of the yeast proteasome in different conformational states (Wehmer et al. PNAS 2017). These models provide the first atomic insights as to how ATP hydrolysis in the engine of the proteasome unwinds proteins and steers them towards the degradation chamber.
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