Signaling by Covalent Heterodimers of Interferon-Î

Interferon-γ (IFN-γ) and its receptor complex are dimeric and bilaterally symmetric. We created mutants of IFN-γ that bind only one IFN-γR1 chain per dimer molecule (called a monovalent IFN-γ) to see if the interaction of IFN-γ with one-half of the receptor complex is sufficient for bioactivit...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-07, Vol.275 (30), p.22995
Main Authors: Christopher D. Krause, Charles A. Lunn, Lara S. Izotova, Olga Mirochnitchenko, Sergei V. Kotenko, Daniel J. Lundell, Satwant K. Narula, Sidney Pestka
Format: Article
Language:English
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Summary:Interferon-γ (IFN-γ) and its receptor complex are dimeric and bilaterally symmetric. We created mutants of IFN-γ that bind only one IFN-γR1 chain per dimer molecule (called a monovalent IFN-γ) to see if the interaction of IFN-γ with one-half of the receptor complex is sufficient for bioactivity. Mutating a receptor-binding sequence in either AB loop of a covalent dimer of IFN-γ yielded two monovalent IFN-γs, γ m -γ and γ-γ m , which cross-link to only a single soluble IFN-γR1 molecule in solution and on the cell surface. Monovalent IFN-γ competes fully with wild type IFN-γ for binding to U937 cells but only at a greater than 100-fold higher concentration than wild type IFN-γ. Monovalent IFN-γ had anti-vesicular stomatitis virus activity and antiproliferative activity, and it induced major histocompatibility complex class I and class II (HLA-DR) expression. In contrast, the maximal levels of activated Stat1α produced by monovalent IFN-γs after 15 min were never more than half of those produced by either wild type or covalent IFN-γs in human cell lines. These data indicate that while monovalent IFN-γ activates only one-half of a four-chain receptor complex, this is sufficient for Stat1α activation, major histocompatibility complex class I surface antigen induction, and antiviral and antiproliferative activities. Thus, while interaction with both halves of the receptor complex is required for high affinity binding of IFN-γ and efficient signal transduction, interaction with only one-half of the receptor complex is sufficient to initiate signal transduction.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M909607199