Reactome | IFN alpha/beta binds to IFNAR2

IFN alpha/beta binds to IFNAR2

Stable Identifier

R-HSA-909720

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

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The ligand IFNalpha/beta (IFNA/B), interacts independently with the two interferon receptor subunits. Based on detailed binding studies with the extracellular domains of the receptor subunits tethered onto solid-supported membranes, a two-step binding mechanism was experimentally confirmed, where the ligand binds first to one of the receptor subunits and then recruits the second subunit (Gavutis et al. 2005). The efficiency of recruitment of the IFNA receptor subunits by the IFN ligand depends on the absolute and relative concentration of the receptor subunits.
IFNAR2 chain constitutively associates with JAK1 kinase in its cytoplasmic domain. In addition IFNAR2 also binds STAT2 in a constitutive manner and this interaction is biochemically different from the interaction of STAT2 with phosphorylated IFNAR1. Although this interaction facilitates the recruitment of STAT2 to the receptors, the biological significance of this constitutive STAT2 interaction to IFNAR2 remains unclear (Nguyen et al, 2002). IFNAR2 not only associates with STAT2, but also with STAT1 and this binding of STAT1 to IFNAR2 depends on the presence of STAT2 but not vice versa.
IFNA/B may first bind to the high-affinity subunit IFNAR2 and subsequently recruit IFNAR1 in a transient fashion (Lamken et al. 2004). Different type I IFNs interact differently with the two IFNA receptor (IFNAR) subunits, IFNB generates a more stable signaling complex than IFNA subtypes. The interaction between IFNalpha2 (IFNA2) and IFNAR2 has an affinity in the nM range, whereas the affinity of the interaction with INFB is about tenfold tighter.

Literature References

PubMed ID	Title	Journal	Year
12842042	The human type I interferon receptor: NMR structure reveals the molecular basis of ligand binding Schreiber, G, Anglister, J, Levy, R, Quadt, SR, Chill, JH	Structure	2003
10395669	Determination of residues involved in ligand binding and signal transmission in the human IFN-alpha receptor 2 Ow, A, Gibbs, V, Jin Kim, K, Chuntharapai, A, Marsters, S, De Vos, A, Lu, J, Ashkenazi, A	J Immunol	1999
9334213	A region of the beta subunit of the interferon alpha receptor different from box 1 interacts with Jak1 and is sufficient to activate the Jak-Stat pathway and induce an antiviral state Krolewski, J, Colamonici, OR, Yan, H, Pitha, P, Fish, E, Platanias, LC, Witte, M, Domanski, P, Nadeau, OW	J Biol Chem	1997
15312780	Ligand-induced assembling of the type I interferon receptor on supported lipid bilayers Piehler, J, Gavutis, M, Lata, S, Lamken, P	J Mol Biol	2004
15778442	Lateral ligand-receptor interactions on membranes probed by simultaneous fluorescence-interference detection Piehler, J, Gavutis, M, Lata, S, Lamken, P, Müller, P	Biophys J	2005
9121453	Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling Stark, GR, Kerr, IM, Li, X, Leung, S	Mol Cell Biol	1997
17969444	The receptor of the type I interferon family Pellegrini, S, Piehler, J, Schreiber, G, Uzé, G	Curr Top Microbiol Immunol	2007