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    • Mapping N- to C-terminal Allosteric Coupling Through Disruption of a Putative CD74 Activation Site in D-dopachrome Tautomerase.

    Emily Chen,Vinnie Widjaja,Gregory Kyro,Brandon Allen,Pragnya Das,Varsha M. Prahaladan,Vineet Bhandari,Elias J. Lolis,Victor S. Batista,George P. Lisi

    JOURNAL OF BIOLOGICAL CHEMISTRY（2023）

    Brown Univ

    Cited 3|Views40
    Abstract
    The macrophage migration inhibitory factor (MIF) protein family consists of MIF and D-dopachrome tautomerase (also known as MIF-2). These homologs share 34% sequence identity while maintaining nearly indistinguishable tertiary and quaternary structure, which is likely a major contributor to their overlapping functions, including the binding and activation of the cluster of differentiation 74 (CD74) receptor to mediate inflammation. Previously, we investigated a novel allosteric site, Tyr99, that modulated N-terminal catalytic activity in MIF through a "pathway" of dynamically coupled residues. In a comparative study, we revealed an analogous allosteric pathway in MIF-2 despite its unique primary sequence. Disruptions of the MIF and MIF-2 N termini also diminished CD74 activation at the C terminus, though the receptor activation site is not fully defined in MIF-2. In this study, we use site-directed in vitro and in vivo biochemistry to explore the putative CD74 activation region of MIF-2 based on homology to MIF. We also confirm its reciprocal structural coupling to the MIF-2 allosteric site and N-terminal enzymatic site. Thus, we provide further insight into the CD74 activation site of MIF-2 and its allosteric coupling for immunoregulation.
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    Key words
    NMR,allostery,cytokine,protein dynamics,receptor activation
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