Dr. George Lisi

Brown University

Hosted by: Vincenzo Venditti

**BioPhysical**

"Allosteric and Redox-dependent Regulation of MIF through Molecular Space and Time"

Abstract:

Macrophage migration inhibitory factor (MIF) is a multifunctional immunoregulatory protein that is a key player in the innate immune response. Despite its symmetric trimer structure composed of small, identical protein subunits, MIF contains three enzymatic active sites, a pro-inflammatory receptor binding site, and is implicated in more than 30 protein-protein interactions and diseases.  MIF is implicated in nearly all inflammatory diseases and several cancers, though the mechanism by which MIF engages in promiscuous interactions with substrates and partner proteins is unclear at the biophysical level, hampering the visualization and targeting of MIF disease states. This talk will describe the structural and dynamic factors that facilitate multi-domain crosstalk and control multiple biological activities in MIF and its homologs. Primarily using solution NMR, the highly dynamic MIF structure will be connected to rearrangements that tune its specific catalytic and pro-inflammatory functions.

A secondary focus will be on efforts to leverage biochemical stimuli such as redox conditions and mutations to understand altered MIF structures and signatures of its “disease states.” NMR spectroscopy will reveal real-time, redox-dependent alterations to the MIF solution structure, and through mass spectrometry, detect residue-level modifications that acts as “molecular switches” for selective binding. Biophysical studies implicate redox-dependent structural dynamics as a means to toggle the MIF functions, and these motions are leveraged in the discovery of latent allosteric sites through mutational analysis. A disruption of redox-dependent structural triggers within MIF attenuate its pro-inflammatory CD74 receptor activation in vivo, suggesting sites of redox sensitivity can be targets for structure-based drug design aimed at modulating MIF its pathological function.

Bio:

George Lisi received a Ph.D. in chemistry at Dartmouth College, working under the co-mentorship of Dean Wilcox and Kate Pletneva. At Dartmouth, he studied the active site architecture and allosteric assembly of enzymes with EPR spectroscopy, calorimetry, and stopped-flow kinetics. He then moved to the Department of Chemistry at Yale University for a postdoc with Pat Loria, where he studied the structures and motions of large enzymes with NMR. Specifically, he trained in spin relaxation methods and synergistic NMR-computational applications to long-range allosteric crosstalk. He began a faculty position at Brown University in September of 2018 and is currently the Thomas J. & Alice M. Tisch Assistant Professor in the Department of Molecular Biology, Cell Biology & Biochemistry and an affiliate faculty member in the Department of Chemistry. The Lisi lab studies the chemistry and structural biology of enzyme complexes, most notably the first NMR studies of the CRISPR-Cas9 enzyme machine and several promiscuous immunoregulatory enzymes.