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Physical Chemistry Seminar: Dr. Mike Thompson, UC San Francisco (Host: Lynette Cegelski)

Mike Thompson Headshot
January 29, 2019 - 4:30pm to 5:30pm
Sapp Center Lecture Hall

Physical Chemistry Seminar: Dr. Mike Thompson, UC San Francisco

About the Seminar

"Turning Up the Heat on Dynamic Proteins: Observing molecular motion in real time with temperature-jump X-ray crystallography and solution scattering"

The importance of dynamics for protein function is widely appreciated; however, it remains challenging to understand, in atomic detail, how a molecule’s biological activity is enabled by the physical coupling of its conformational fluctuations across varied length and time scales. For example, the catalytic cycles of enzymes often involve conformational rearrangements that facilitate sequential steps of substrate binding, chemical transformation, and product release. Consequently, the elucidation of their functional mechanisms requires high-resolution information about both structure and dynamics, which can be difficult to obtain in practice. To this end, time-resolved X-ray crystallography and solution scattering experiments, in which fast X-ray pulses are used to measure structural changes of macromolecules in real time, are powerful tools for studying dynamic proteins because they provide simultaneous structural and kinetic data. Unfortunately, their widespread use in structural biology has been limited by a major technical hurdle: in order to observe dynamic behavior from an ensemble-averaged experimental measurement, it is necessary to synchronize conformational changes for a significant fraction of molecules in the sample. In my seminar, I will describe how we have been able to overcome this challenge by exploiting the temperature-sensitivity of protein conformational ensembles. I will share the results of our first temperature-jump (T-jump) crystallography and SAXS/WAXS experiments in which a pulsed infrared laser was used to rapidly heat soluble or crystallized proteins, initiating conformational dynamics that were subsequently monitored in real time using ultrafast X-ray pulses from next generation light sources, including both synchrotrons and free-electron lasers. I will show that these early experiments effectively captured signatures of specific functional motions in two model enzymes, cyclophilin A and lysozyme, validating the use of T-jump as a universal perturbation method for time-resolved studies of protein conformational dynamics. I will conclude my presentation by briefly describing future prospects for using T-jump X-ray methods to address important questions about dynamic biomolecular systems, with an emphasis on protein molecules that protect us against neurodegenerative disease by detecting and responding to cellular stresses.

About the Speaker

Mike obtained his Bachelor's degree in Molecular and Cell Biology from UC Berkeley in 2007, where he was introduced to structural biology and X-ray crystallography while working as a research assistant in Tom Alber’s laboratory. After receiving his undergraduate degree, he completed his graduate studies at UCLA under the mentorship of Todd Yeates and received his Ph.D. in Biochemistry and Molecular Biology in 2014. As a graduate student, Mike investigated the role of conformational heterogeneity in expanding the functional diversity of a key family of proteins that define a widespread class of prokaryotic organelles collectively known as “bacterial microcompartments.” Since 2014, Mike has been a Postdoctoral Fellow with James Fraser at UCSF, where he has focused on developing and applying new methodologies for understanding how proteins function by dynamically interconverting between different conformational states. His postdoctoral research has been supported by a postdoctoral fellowship from the BioXFEL Science and Technology Center (NSF), a Kirschstein NRSA (F32) fellowship from NIH/NHLBI, and an Independent Postdoctoral Research Award from the UCSF Program in Breakthrough Biomedical Research (PBBR). Mike's long-term scientific goal is to push the limits of experimental structural biology, in order to deepen our understanding of how genetic mutations lead to human diseases, and to create new opportunities for drug discovery and protein engineering.

 

This event belongs to the following series