ORIGINAL ARTICLE

Cell Research (2006)16:45-54
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Preassembly and ligand-induced restructuring of the chains of the IFN-γ receptor complex: the roles of Jak kinases, Stat1 and the receptor chains

Christopher D Krause¹, Natasha Lavnikova¹, Junxia Xie¹, Erwen Mei², Olga V Mirochnitchenko¹, Yiwei Jia³, Robin M Hochstrasser², Sidney Pestka^1,4,5

¹Department of Molecular Genetics, Microbiology and Immunology, The University of Medicine and Dentistry of New Jersey -Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ 08854, USA;
²Regional Laser Biotechnology Laboratories, Department of Chemistry, The University of Pennsylvania, Philadelphia, PA 19103, USA;
³Olympus America Inc., SEG, Two Corporate Center Drive, Melville, NY 11747-3157, USA; ⁴Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903-2681, USA; ⁵PBL Biomedical Laboratories, 131 Ethel Road West, Suite 6, Piscataway, NJ 08854-5900, USA

Correspondence: Sidney Pestka Tel: +732-235-4567; Fax: +732-235-5223; E-mail: pestka@umdnj.edu

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Abstract

We previously demonstrated using noninvasive technologies that the interferon-gamma (IFN-γ) receptor complex is preassembled [1]. In this report we determined how the receptor complex is preassembled and how the ligand-mediated conformational changes occur. The interaction of Stat1 with IFN-γR1 results in a conformational change localized to IFN-γR1. Jak1 but not Jak2 is required for the two chains of the IFN-γ receptor complex (IFN-γR1 and IFN-γR2) to interact; however, the presence of both Jak1 and Jak2 is required to see any ligand-dependant conformational change. Two IFN-γR2 chains interact through species-specific determinants in their extracellular domains. Finally, these determinants also participate in the interaction of IFN-γR2 with IFN-γR1. These results agree with a detailed model of the IFN-γ receptor that requires the receptor chains to be pre-associated constitutively for the receptor to be active.

Cell Research (2006) 16:55-69. doi:10.1038/sj.cr.7310008; published online 16 January 2006

Keywords: interferon-gamma, receptors, fluorescence resonance energy transfer, interactions, cytokines, species specificity, Janus kinase, Stat protein, mutagenesis