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Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions: Evidence for Partial Allosteric Agonism in Comparison to CXCL12

Journal of Biological Chemistry. 2016 May 19. pii: jbc.M116.717751. DOI: 10.1074/jbc.M116.717751. [Epub ahead of print]

Authors/Editors: Rajasekaran D, Gröning S, Schmitz C, Zierow S, Drucker N, Bakou M, Kohl K, Mertens A, Lue H, Weber C, Xiao A, Luker G, Kapurniotu A, Lolis E, Bernhagen J
Publication Date: 2016


An emerging number of non-chemokine mediators are found to bind to classical chemokine receptors and to elicit critical biological responses. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exhibits chemokine-like activities through non-cognate interactions with the chemokine receptors CXCR2 and CXCR4, in addition to activating the type-II receptor CD74. Activation of the MIF-CXCR2 and -CXCR4 axes promotes leukocyte recruitment, mediating MIF’s exacerbating role in atherosclerosis and contributing to the wealth of other MIF biological activities. While the structural basis of the MIF-CXCR2 interaction has been well studied and was found to engage a pseudo-ELR and an N-like loop motif, nothing is known about the regions of CXCR4 and MIF that are involved in binding to each other. Using a genetic strain of S. cerevisiae that expresses a functional CXCR4 receptor, site-specific mutagenesis, hybrid CXCR3/CXCR4 receptors, pharmacological reagents, peptide array analysis, chemotaxis, fluorescence spectroscopy and circular dichroism, we provide novel molecular information about the structural elements that govern the interaction between MIF and CXCR4. The data identify similarities with classical chemokine-receptor interactions but also provide evidence for a partial allosteric agonist compared to CXCL12 that is possible due to the two binding sites of CXCR4.


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