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J Biol Chem, Vol. 273, Issue 7, 4046-4051, February 13, 1998
Receptor-binding Domain on the
TYK2 Kinase
,,,
From the Interferons and cytokines modulate gene
expression via a simple, direct signaling pathway containing receptors,
JAK tyrosine kinases, and STAT transcription factors. The
interferon- Department of Pathology and the Irving
Comprehensive Cancer Center, Columbia University, College of
Physicians and Surgeons, New York, New York 10032 and the ¶ Public
Health Research Institute, New York, New York 10016
pathway is a model for these cascades. Two receptors,
IFNaR1 and IFNaR2, associate exclusively in a constitutive manner with
two JAK proteins, TYK2 and JAK1, respectively. Defining the molecular
interface between JAK proteins and their receptors is critical to
understanding the signaling pathway and may contribute to the
development of novel therapeutics. This report defines the IFNaR1
interaction domain on TYK2. In vitro binding studies
demonstrate that the amino-terminal half of TYK2, which is ~600 amino
acids long and contains JAK homology (JH) domains 3-7, comprises the
maximal binding domain for IFNaR1. A fragment containing amino acids
171-601 (JH3-6) also binds IFNaR1, but with reduced affinity.
Glutathione S-transferase-TYK2 fusion proteins
approximating either the JH6 or JH3 domain affinity-precipitate IFNaR1,
suggesting that these are major sites of interaction within the larger
binding domain. TYK2 amino acids 1-601 act in a dominant manner to
inhibit the transcription of an interferon--dependent
reporter gene, presumably by displacing endogenous TYK2 from the
receptor. This same fragment inhibits
interferon--dependent tyrosine phosphorylation of TYK2, STAT1, and STAT2.
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