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Abstract:
To carry out essential functions in every cell, proteins need to be correctly folded and localized to the right place at the right time. I will present two stories about protein translocation that combine structure and function to characterize large macromolecular complexes. First, one important way that bacterial pathogens establish infections is by transporting effector proteins into a host cell across multiple membranes. Bacteria have evolved elaborate strategies to accomplish this, including the Type IV Secretion System (T4SS). The Legionella pneumophila Dot/Icm T4SS translocates hundreds of effector proteins into the host cell and is essential for pathogenesis, leading to the potentially fatal pneumonia Legionnaires’ Disease. The ~30 components of the system have been thoroughly catalogued, but our understanding of how they fit together and do the physical work of moving substrate proteins lags behind. Using biochemistry, genetics, and cryo-electron microscopy, I have isolated the core complex of the Dot/Icm T4SS and determined its macromolecular structure. I have uncovered distinctive structural characteristics and identified proteins not previously known to be part of the complex. Second, bacteria, yeast, and plants have homologous protein machinery to disrupt protein aggregates. Understanding how these macromolecular machines, known as disaggregases, couple the energy of ATP binding and hydrolysis to the mechanical work of protein translocation may lead to novel methods of treating and preventing aggregation in the context of neurodegenerative disease. Using biophysical techniques to test a mechanistic hypothesis that was based on structures of the disaggregase resulted in a new understanding of the mechanism of protein translocation by the disaggregase.