The N-terminus of MIF Controls the Flexibility of Specific β-sheet Residues Resulting in Dynamic Regulation of CD74 Activation

William Knox Holt Memorial Library and Learning Center

Macrophage migration inhibitory factor (MIF) is a pleiotropic protein with catalytic, CD74, CXCR2, CXCR4, and nuclease activities that contribute to the pathology of various inflammatory disorders, cardiovascular diseases, and cancer. The majority of MIF-triggered pathological conditions are associated with the activation of CD74, MIF’s cell surface receptor. The mechanistic details of MIF-induced activation of CD74 were mostly unknown until recently where it was shown that intramolecular dynamic signals transmitted from an allosteric center regulate the CD74activation site on MIF’s surface. Via backbone dynamic signals, the same center also controls the enzymatic pocket of MIF and more specifically the catalytically active residue Pro1, which serves as the sole target for the discovery and development of CD74 antagonists. Through these findings, the need to explore the dynamic communication between the enzymatic and CD74 activation sites became apparent. By utilizing molecular dynamics(MD) simulations, nuclear magnetic resonance (NMR) and circular dichroism (CD) experiments, we investigated how changes of the N-terminal flexibility influence the surface of MIF. Our findings support that dynamic signals transmitted from the enzymatic site reach the surface of MIF, affecting CD74 activation. For the first time, such data were able to provide dynamic profiles that explain the differences between MIF variants serving as CD74 agonists or antagonists.