Identification of Residues of the IFNAR1 Chain of the Type I Human Interferon Receptor Critical for Ligand Binding and Biological Activity
Autor: | Chantal Cajean-Feroldi, Jean-Louis Escary, Pierre Nardeux, Jacqueline Guymarho, Pascal Sempe, Florence Nosal, Florence Baychelier, Michael G. Tovey, Xavier Gallet, Pierre Eid |
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Rok vydání: | 2004 |
Předmět: |
Models
Molecular Receptor complex DNA Mutational Analysis Molecular Sequence Data Receptor Interferon alpha-beta Biology Ligands Transfection Biochemistry Cell Line Mice Protein structure Serine Animals Humans Protein Isoforms Amino Acid Sequence Binding site Receptor Peptide sequence Receptors Interferon Sequence Homology Amino Acid Lysine Cell Membrane Mutagenesis Tryptophan Antibodies Monoclonal Membrane Proteins Valine Biological activity Peptide Fragments Transmembrane protein Protein Structure Tertiary Interferon Type I Tyrosine Binding Sites Antibody Extracellular Space Protein Binding Signal Transduction |
Zdroj: | Biochemistry. 43:12498-12512 |
ISSN: | 1520-4995 0006-2960 |
Popis: | 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)FSSLKLNVY(70) 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-alpha binding and signaling and establishment of biological activity. Mutagenesis of peptide (278)LRV in the third subdomain shows that these residues are critical for IFN-alpha-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-alpha/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-alpha 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-alpha subtypes. |
Databáze: | OpenAIRE |
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