bi049606g_si_001.pdf (71.57 kB)
Download fileNMR Backbone Dynamics of the Human Type I Interferon Binding Subunit, a Representative Cytokine Receptor†
journal contribution
posted on 10.08.2004, 00:00 by Jordan H. Chill, Sabine R. Quadt, Jacob AnglisterThe antiviral and antiproliferative activities of type I interferons (IFNs) are mediated by a
common receptor, and its second subunit (IFNAR2) exhibits nanomolar affinity to both IFNα and IFNβ
subtypes. We have previously determined the structure of the IFN-binding extracellular domain of IFNAR2
(IFNAR2-EC) using multidimensional NMR [Chill, J. H., Quadt, S. R., Levy, R., Schreiber, G. E., and
Anglister, J. (2003) Structure 11, 791−802], showing it to comprise two fibronectin domains linked by
a hinge. As the first cytokine receptor structure determined in the unliganded state and in solution, IFNAR2-EC offers an opportunity to characterize the dynamics of the cytokine receptor family and their correlation
to biological function. Backbone dynamics of IFNAR2-EC were investigated using 15N relaxation at 11.74
and 18.79 T, and measurements of residual dipolar couplings (RDCs). Dynamics of the binding site
distinguish between rigid structural domains, which stabilize the binding site conformation, and a more
flexible binding interface which interacts with the ligand. Measurements of diffusional anisotropy and
RDCs and model-free analysis all show that the backbone of the hinge interdomain region of IFNAR2-EC is rigid on the picosecond to nanosecond time scale. Signal transduction in cytokines receptors is
initiated by ligand-induced juxtaposition of the two receptor subunits, triggering the mutual phosphorylation
of kinases associated to their cytoplasmic domains. The rigidity of the hinge ensures correct positioning
of the receptor subunits in the ternary signaling complex and modulates the interaction between kinases
in the cytoplasm, thereby controlling the rate and efficiency of phosphorylation.