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Publication Abstract from PubMed

The MIF family of cytokines contain multiple ligand binding sites and mediate immunomodulatory processes through an undefined mechanism(s). Previously, we reported a dynamic relay connecting the MIF catalytic site to an allosteric site at its solvent channel. Despite structural and functional similarity, the MIF homolog D-dopachrome tautomerase (also called MIF-2) has low sequence identity (35%), prompting the question of whether this dynamic regulatory network is conserved. Here, we establish the structural basis of an allosteric site in MIF-2, showing with solution NMR that dynamic communication is preserved in MIF-2 despite differences in the primary sequence. X-ray crystallography and NMR detail the structural consequences of perturbing residues in this pathway, which include conformational changes surrounding the allosteric site, despite global preservation of the MIF-2 fold. Molecular simulations reveal MIF-2 to contain a comparable hydrogen bond network to that of MIF, which was previously hypothesized to influence catalytic activity by modulating the strength of allosteric coupling. Disruption of the allosteric relay by mutagenesis also attenuates MIF-2 enzymatic activity in vitro and the activation of the CD74 receptor in vivo, highlighting a conserved point of control for non-overlapping functions in the MIF superfamily.

A Structurally Preserved Allosteric Site in the MIF Superfamily Affects Enzymatic Activity and CD74 Activation in D-dopachrome Tautomerase.,Chen E, Reiss K, Shah D, Manjula R, Allen B, Murphy EL, Murphy JW, Batista VS, Bhandari V, Lolis EJ, Lisi GP J Biol Chem. 2021 Aug 9:101061. doi: 10.1016/j.jbc.2021.101061. PMID:34384784^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.