2016
DOI: 10.1074/jbc.m115.686071
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Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

Abstract: Type I interferons serve as the first line of defense against pathogen invasion. Binding of IFNs to its receptors, IFNAR1 and IFNAR2, is leading to activation of the IFN response. To determine whether structural perturbations observed during binding are propagated to the cytoplasmic domain, multiple mutations were introduced into the transmembrane helix and its surroundings. Insertion of one to five alanine residues near either the N or C terminus of the transmembrane domain (TMD) likely promotes a rotation of… Show more

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Cited by 15 publications
(21 citation statements)
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“…Mechanistically, these results may, therefore, point to a role for the identified IFN-␤-IFNAR1-SD3 interface in differentially regulating or mediating alternative IFN-␤-IFNAR1-driven signaling events or pathways. Our data, demonstrating the functional importance of residues at the IFN-␤-IFNAR1-SD3 interface, are in contrast to alanine mutations introduced to the (juxta) transmembrane region which predictably had no effect on IFN binding affinity or signaling (28).…”
Section: Hot Spot On Ifnar1 Underpins Ifn-␤ Signalingcontrasting
confidence: 55%
“…Mechanistically, these results may, therefore, point to a role for the identified IFN-␤-IFNAR1-SD3 interface in differentially regulating or mediating alternative IFN-␤-IFNAR1-driven signaling events or pathways. Our data, demonstrating the functional importance of residues at the IFN-␤-IFNAR1-SD3 interface, are in contrast to alanine mutations introduced to the (juxta) transmembrane region which predictably had no effect on IFN binding affinity or signaling (28).…”
Section: Hot Spot On Ifnar1 Underpins Ifn-␤ Signalingcontrasting
confidence: 55%
“…As shown by us previously, it is unlikely that the movements of the EC domain will affect the arrangement of the IC domain (Sharma et al , 2016). However, such movements may be essential to mediating ligand specificity and binding affinity, and may affect signaling functions.…”
Section: Introductionmentioning
confidence: 78%
“…IFNs induce a cellular response upon forming a ternary complex with two surface receptors, IFNAR1 and IFNAR2 (Thomas et al , 2011). Binding of IFN to the extracellular (EC) domains of these receptors results in bringing their intracellular (IC) domains into close proximity, upon which their associated tyrosine kinases (JAKs) phosphorylate IC receptor chains and associated effector proteins (Stark and Darnell, 2012; Sharma et al , 2016). …”
Section: Introductionmentioning
confidence: 99%
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