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

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Abstract

The interaction of IFN-β with its receptor IFNAR1 is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. While 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 (SD)-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 which is centered on IFNAR1 tyrosine residues Y240 and Y274 binding the C-terminal and N-terminal of 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 Y240 and Y274 interacting with IFN-β residues F63, L64, E77, T78, V81, R82 that underlie IFN-β-IFNAR1 mediated signaling and biological processes.
Original languageEnglish
Pages (from-to)7554-7565
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number18
DOIs
Publication statusPublished - 5 May 2017

Cite this

@article{c0fca935283147a5bd53d0cf0b3b3900,
title = "A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling",
abstract = "The interaction of IFN-β with its receptor IFNAR1 is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. While 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 (SD)-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 which is centered on IFNAR1 tyrosine residues Y240 and Y274 binding the C-terminal and N-terminal of 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 Y240 and Y274 interacting with IFN-β residues F63, L64, E77, T78, V81, R82 that underlie IFN-β-IFNAR1 mediated signaling and biological processes.",
author = "{de Weerd}, {Nicole A.} and Matthews, {Antony Y.} and Pattie, {Phillip R.} and Bourke, {Nollaig M.} and Lim, {San S.} and Vivian, {Julian P.} and Jamie Rossjohn and Hertzog, {Paul J.}",
year = "2017",
month = "5",
day = "5",
doi = "10.1074/jbc.M116.773788",
language = "English",
volume = "292",
pages = "7554--7565",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
publisher = "American Society for Biochemistry and Molecular Biology",
number = "18",

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TY - JOUR

T1 - A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

AU - de Weerd, Nicole A.

AU - Matthews, Antony Y.

AU - Pattie, Phillip R.

AU - Bourke, Nollaig M.

AU - Lim, San S.

AU - Vivian, Julian P.

AU - Rossjohn, Jamie

AU - Hertzog, Paul J.

PY - 2017/5/5

Y1 - 2017/5/5

N2 - The interaction of IFN-β with its receptor IFNAR1 is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. While 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 (SD)-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 which is centered on IFNAR1 tyrosine residues Y240 and Y274 binding the C-terminal and N-terminal of 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 Y240 and Y274 interacting with IFN-β residues F63, L64, E77, T78, V81, R82 that underlie IFN-β-IFNAR1 mediated signaling and biological processes.

AB - The interaction of IFN-β with its receptor IFNAR1 is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. While 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 (SD)-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 which is centered on IFNAR1 tyrosine residues Y240 and Y274 binding the C-terminal and N-terminal of 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 Y240 and Y274 interacting with IFN-β residues F63, L64, E77, T78, V81, R82 that underlie IFN-β-IFNAR1 mediated signaling and biological processes.

U2 - 10.1074/jbc.M116.773788

DO - 10.1074/jbc.M116.773788

M3 - Article

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SP - 7554

EP - 7565

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 18

ER -