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A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

De Weerd, Nicola A., Matthews, Anthony Y., Pattie, Philip R., Bourke, Nollaig M., Lim, San S., Vivian, Julian P., Rossjohn, Jamie and Hertzog, Paul J. 2017. A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling. World Journal of Biological Chemistry 292 , pp. 7554-7565. 10.1074/jbc.M116.773788

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The interaction of IFN-β with its receptor IFNAR1 (interferon α/β receptor subunit 1) is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. Whereas it is established that IFNAR1 is an essential component of the IFNAR signaling complex, the key residues underpinning the IFN-β-IFNAR1 interaction are unknown. Guided by the crystal structure of the IFN-β-IFNAR1 complex, we used truncation variants and site-directed mutagenesis to investigate domains and residues enabling complexation of IFN-β to IFNAR1. We have identified an interface on IFNAR1-subdomain-3 that is differentially utilized by IFN-β and IFN-α for signal transduction. We used surface plasmon resonance and cell-based assays to investigate this important IFN-β binding interface that is centered on IFNAR1 residues Tyr240 and Tyr274 binding the C and N termini of the B and C helices of IFN-β, respectively. Using IFNAR1 and IFN-β variants, we show that this interface contributes significantly to the affinity of IFN-β for IFNAR1, its ability to activate STAT1, the expression of interferon stimulated genes, and ultimately to the anti-viral and anti-proliferative properties of IFN-β. These results identify a key interface created by IFNAR1 residues Tyr240 and Tyr274 interacting with IFN-β residues Phe63, Leu64, Glu77, Thr78, Val81, and Arg82 that underlie IFN-β-IFNAR1-mediated signaling and biological processes.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Baishideng Publishing Group Co. Limited
ISSN: 1949-8454
Date of First Compliant Deposit: 30 May 2017
Last Modified: 19 Oct 2019 11:02

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