LSI Seminar Series: Susan M. Lea, Ph.D., National Cancer Institute
Structural basis of directional switching by the bacterial flagellum
The bacterial flagellum is a macromolecular protein complex that harvests energy from ion-flow across the inner membrane to power bacterial swimming in viscous fluids via rotation of the flagellar filament. Bacteria such as Salmonella enterica are capable of bi-directional flagellar rotation even though ion flow is uni-directional. How uni-directional ion movement through the inner membrane is utilized by this macromolecular machine to drive bi-directional flagellar rotation is not understood, but a chemotactic response regulator in the cytoplasm is known to reverse the direction of rotation. We will present cryo-EM structures of intact Salmonella flagellar basal bodies, including the cytoplasmic complexes required for power transmission, in conformations representing both directions of rotation. The structures reveal that the conformational changes required for switching the direction of rotation involve 180 degree rotations of both the N- and C-terminal domains of the FliG protein. Combining these models with a new, high-resolution, cryo-EM structure of the MotA5B2 stator, in complex with the C-terminal domain of FliG, reveals how uni-directional ion-flow across the inner membrane is used to accomplish bi-directional rotation of the flagellum.
Susan Lea’s research career started with a Ph.D. in the Laboratory of Molecular Biophysics (1990-1993) at the University of Oxford with David Stuart, using cutting-edge X-ray crystallography to study foot and mouth disease virus. In 1995, she established her independent group in the Department of Biochemistry, Oxford, with one of the first Royal Society Dorothy Hodgkin Fellowships. At that time, the group focused on structural and functional studies of human enteroviruses and their receptors, which commonly complement system molecules. In 1999, Lea was appointed to a tenured academic position in the Department of Biochemistry, Oxford, and continued to grow a program increasingly focused on human complement system regulation and pathogen evasion. This led to an interest in bacterial pathogenesis systems, which expanded when she moved her group to the Sir William Dunn School of Pathology, Oxford, in 2000. She was appointed to the Chair in Microbiology in that Department in 2016. Susan was elected a member of the European Molecular Biology Organisation (EMBO) in 2015, a Fellow of the Academy of Medical Sciences in 2017, The American Academy of Microbiology and of the Royal Society in 2022.