IDENTIFICATION OF AMINO-ACID-RESIDUES CRITICAL FOR THE SRC-HOMOLOGY-2DOMAIN-DEPENDENT DOCKING OF STAT2 TO THE INTERFERON-ALPHA RECEPTOR

The interaction between Src-homology 2 domains (SH2) domains and phosp horylated tyrosine residues serves a critical role in intracellular si gnaling. In addition to the phosphotyrosine, adjacent residues are cri tical mediators of the specificity of this interaction, Upon treatment of cells with interferon alpha (IFN alpha), the IFNaR1 subunit of the IFN alpha receptor becomes tyrosine phosphorylated at position 466, T he region surrounding phosphorylated tyrosine 466 subsequently acts as a docking site for the SH2 domain of Stat2, facilitating phosphorylat ion of the latter and, thus, the transduction of the IFNa signal, In t his report site-specific mutagenesis was employed to analyze the natur e of the interaction between the SH2 domain of Stat2 and the region su rrounding tyrosine 466 on IFNaR1. Mutation of the valine at the +1 pos ition carboxyl-terminal to tyrosine 466 or of the serine at the +5 pos ition inhibits the association of Stat2 with phosphorylated IFNaR1, Mo reover, receptors mutated at either of these two positions act in a do minant manner to decrease IFN alpha signaling, as assayed by both Stat 2 phosphorylation and expression of an IFN alpha-responsive reporter. The demonstration that these two residues are critical in mediating th e interaction between Stat2 and IFNaR1 suggests that STAT proteins mig ht utilize a structurally distinct subset of SH2 domains to mediate si gnal transduction from the cell surface to the nucleus.