Identification of Residues of the IFNAR1 Chain of the Type I Human Interferon Receptor Critical for Ligand Binding and Biological Activity

The antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by two transmembrane receptor subunits, IFNAR1 and IFNAR2. To elucidate the role of IFNAR1 in IFN binding and the establishment of biological activity, specific residues of IFNAR1 were mutated. Residues 62...

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Bibliographic Details
Published in:	Biochemistry (Easton) Vol. 43; no. 39; pp. 12498 - 12512
Main Authors:	Cajean-Feroldi, Chantal, Nosal, Florence, Nardeux, Pierre C, Gallet, Xavier, Guymarho, Jacqueline, Baychelier, Florence, Sempé, Pascal, Tovey, Michael G, Escary, Jean-Louis, Eid, Pierre
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 05-10-2004
Subjects:	Amino Acid Sequence Animals Antibodies, Monoclonal - metabolism Binding Sites, Antibody Cell Line Cell Membrane - genetics Cell Membrane - metabolism DNA Mutational Analysis - methods Extracellular Space - genetics Humans Interferon Type I - metabolism Ligands Lysine - genetics Membrane Proteins Mice Models, Molecular Molecular Sequence Data Peptide Fragments - genetics Peptide Fragments - metabolism Protein Binding - genetics Protein Isoforms - biosynthesis Protein Isoforms - genetics Protein Structure, Tertiary - genetics Receptor, Interferon alpha-beta Receptors, Interferon - biosynthesis Receptors, Interferon - genetics Receptors, Interferon - immunology Receptors, Interferon - metabolism Sequence Homology, Amino Acid Serine - genetics Signal Transduction - genetics Transfection Tryptophan - genetics Tyrosine - genetics Valine - genetics
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Summary:	The antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by two transmembrane receptor subunits, IFNAR1 and IFNAR2. To elucidate the role of IFNAR1 in IFN binding and the establishment of biological activity, specific residues of IFNAR1 were mutated. Residues 62FSSLKLNVY70 of the S5−S6 loop of the N-terminal subdomain of IFNAR1 and tryptophan-129 of the second subdomain of IFNAR1 were shown to be crucial for IFN-α binding and signaling and establishment of biological activity. Mutagenesis of peptide 278LRV in the third subdomain shows that these residues are critical for IFN-α-induced biological activity but not for ligand binding. These data, together with the sequence homology of IFNAR1 with cytokine receptors of known structure and the recently resolved NMR structure of IFNAR2, led to the establishment of a three-dimensional model of the human IFN-α/IFNAR1/IFNAR2 complex. This model predicts that following binding of IFN to IFNAR1 and IFNAR2 the receptor complex assumes a “closed form”, in which the N-terminal domain of IFNAR1 acts as a lid, resulting in the activation of intracellular kinases. Differences in the primary sequence of individual IFN-α subtypes and resulting differences in binding affinity, duration of ligand/receptor association, or both would explain differences in intracellular signal intensities and biological activity observed for individual IFN-α subtypes.
Bibliography:	This work was supported in part by the Association Nouvelles Recherches Biomedicales, Pharma Pacific Pty, and Medarex Inc. istex:56251F51EE796659094006B2F1BBC665CF588F4A ark:/67375/TPS-PLSD6VCT-H ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0006-2960 1520-4995
DOI:	10.1021/bi049111r