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J. Biol. Chem., Vol. 283, Issue 47, 32925-32936, November 21, 2008

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The Stability of the Ternary Interferon-Receptor Complex Rather than the Affinity to the Individual Subunits Dictates Differential Biological Activities^*

Eyal Kalie, Diego A. Jaitin, Yulia Podoplelova, Jacob Piehler, and Gideon Schreiber¹

From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel and Institute of Biochemistry and Cluster of Excellence Macromolecular Complexes, Goethe University, 60438 Frankfurt/Main, Germany

Type I interferons (IFNs) signal for their diverse biological effects by binding a common receptor on target cells, composed of the two transmembrane IFNAR1 and IFNAR2 proteins. We have previously differentially enhanced the antiproliferative activity of IFN by increasing the weak binding affinity of IFN to IFNAR1. In this study, we further explored the affinity interdependencies between the two receptor subunits and the role of IFNAR1 in differential IFN activity. For this purpose, we generated a panel of mutations targeting the IFNAR2 binding site on the background of the IFN2 YNS mutant, which increases the affinity to IFNAR1 by 60-fold, resulting in IFNAR2-to-IFNAR1 binding affinity ratios ranging from 1000:1 to 1:1000. Both the antiproliferative and antiviral potencies of the interferon mutants clearly correlated to the in situ binding IC₅₀ values, independently of the relative contributions of the individual receptors, thus relating to the integral lifetime of the complex. However, the antiproliferative potency correlated throughout the entire range of affinities, as well as with prolonged IFNAR1 receptor down-regulation, whereas the antiviral potency reached a maximum at binding affinities equivalent to that of wild-type IFN2. Our data suggest that (i) the specific activity of interferon is related to the ternary complex binding affinity and not to affinity toward individual receptor components and (ii) although the antiviral pathway is strongly dependent on pSTAT1 activity, the cytostatic effect requires additional mechanisms that may involve IFNAR1 down-regulation. This differential interferon response is ultimately mediated through distinct gene expression profiling.

Received for publication, August 5, 2008 , and in revised form, September 15, 2008.

^* This work was supported by Israel Science Foundation (founded by the Israel Academy of Sciences and Humanities) Grant 633/06 (to G. S.) and Deutsche Forschungsgemeinschaft Grants PI 405/4 and EXC 115 (to J. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Scheme 1 and Figs. S1-S3.

¹ To whom correspondence should be addressed. Tel.: 972-8-934-3249; Fax: 972-8-934-6095; E-mail: gideon.schreiber{at}weizmann.ac.il.

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