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J Biol Chem, Vol. 273, Issue 18, 10919-10925, May 1, 1998

The Heparan Sulfate Binding Sequence of Interferon- Increased the On Rate of the Interferon--Interferon- Receptor Complex Formation

Rabia Sadir, Eric Forest^¶, and Hugues Lortat-Jacob

From the  Institut Pasteur de Lyon, CNRS URA 1459, ^¶ Laboratoire de Spectrométrie de Masse, and  Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale, CNRS UPR 9015, Avenue des Martyrs, 38027 Grenoble Cedex 01, France

Interferon- (IFN), in common with a number of growth factors, binds both to heparan sulfate or heparin-related molecules and to a specific high affinity receptor (IFNR). Using surface plasmon resonance technology, kinetic analysis of the IFN·IFNR complex formation was performed with the extracellular part of IFNR immobilized on a sensor chip. At the sensor chip surface, IFN was bound by two IFNR molecules with an affinity in the nanomolar range (0.68 nM). This binding was characterized by an important on rate, k_on = 7.3 × 10⁶ M¹·s¹, and an off rate, k_off = 5 × 10³·s¹. This binding assay was used to investigate a possible role of heparin in the IFN·IFNR complex formation. In contrast to growth factors for which binding to heparin is usually required for high affinity receptor interaction, we found in this study that IFN bound to heparin displayed a strongly reduced affinity for its receptor. This is consistent with the fact that a cluster of basic amino acids (KTGKRKR, called the C1 domain) in the carboxyl-terminal sequence of the cytokine was involved both in heparin and receptor recognition. To understand how a single domain of IFN could be implicated in two discrete functions (i.e. binding to heparin and to IFNR), we also analyzed in a detailed manner the role of the IFN carboxyl-terminal sequence in receptor binding. Using forms of IFN, with carboxyl terminus truncations of defined regions of the heparin binding sequence, we found that the C1 domain functioned by increasing the on rate of the IFN·IFNR binding reaction but was not otherwise required for the stability of the complex. Interactions between the IFN carboxyl-terminal domain and IFNR could increased the association rate of the reaction either by increasing the number of encounters between the two molecules or by favoring productive collisions. The mechanisms by which heparan sulfate regulates IFN activity may thus include both control of selective protease cleavage events, which directly affect the cytokine activity, and also an ability to modulate the interaction of IFN with the IFNR via competitive binding to the C1 domain.

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