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Molecular and Cellular Biology, March 2006, p. 1888-1897, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1888-1897.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Inquiring into the Differential Action of Interferons (IFNs): an IFN-{alpha}2 Mutant with Enhanced Affinity to IFNAR1 Is Functionally Similar to IFN-ß

Diego A. Jaitin,1 Laila C. Roisman,1 Eva Jaks,2 Martynas Gavutis,2 Jacob Piehler,2 Jose Van der Heyden,3 Gilles Uze,3 and Gideon Schreiber1*

Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel,1 Institute of Biochemistry, Goethe University Frankfurt/Main, Frankfurt/Main, Germany,2 Laboratory of Antiviral Defenses, CNRS UMR 5124, Montpellier, France3

Received 20 September 2005/ Returned for modification 28 November 2005/ Accepted 13 December 2005

Alpha and beta interferons (IFN-{alpha} and IFN-ß) are multifunctional cytokines that exhibit differential activities through a common receptor composed of the subunits IFNAR1 and IFNAR2. Here we combined biophysical and functional studies to explore the mechanism that allows the alpha and beta IFNs to act differentially. For this purpose, we have engineered an IFN-{alpha}2 triple mutant termed the HEQ mutant that mimics the biological properties of IFN-ß. Compared to wild-type (wt) IFN-{alpha}2, the HEQ mutant confers a 30-fold higher binding affinity towards IFNAR1, comparable to that measured for IFN-ß, resulting in a much higher stability of the ternary complex as measured on model membranes. The HEQ mutant, like IFN-ß, promotes a differentially higher antiproliferative effect than antiviral activity. Both bring on a down-regulation of the IFNAR2 receptor upon induction, confirming an increased ternary complex stability of the plasma membrane. Oligonucleotide microarray experiments showed similar gene transcription profiles induced by the HEQ mutant and IFN-ß and higher levels of gene induction or repression than those for wt IFN-{alpha}2. Thus, we show that the differential activities of IFN-ß are directly related to the binding affinity for IFNAR1. Conservation of the residues mutated in the HEQ mutant within IFN-{alpha} subtypes suggests that IFN-{alpha} has evolved to bind IFNAR1 weakly, apparently to sustain differential levels of biological activities compared to those induced by IFN-ß.

* Corresponding author. Mailing address: Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel. Phone: 972 8 934 3249. Fax: 972 8 934 6095. E-mail: gideon.schreiber{at}weizmann.ac.il.

Molecular and Cellular Biology, March 2006, p. 1888-1897, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1888-1897.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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