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Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
The sequence I/VxYxxL, often referred to as an immunoreceptor tyrosine-based inhibition motif (ITIM), binds to the C-terminal Src homology 2 domain of the tyrosine phosphatase SHP-1. Conserved residues N-terminal of the tyrosine are not ordinarily found in other Src homology 2 domain binding motifs. The inhibitory forms of killer cell Ig-like receptors (KIR) contain two ITIMs. The role of each ITIM, and of the conserved residues upstream of the tyrosine, in the inhibition of NK cells was tested by vaccinia virus-mediated expression of mutant KIRs. Substitution of the tyrosine in the membrane-proximal ITIM abrogated the ability of KIR to block Ab-dependent cellular cytotoxicity, whereas mutation of the membrane-distal ITIM tyrosine had little effect. Substitution of the conserved hydrophobic amino acid that was located two residues N-terminal to the tyrosine weakened, but did not eliminate, the function of the receptor. In contrast, these substitutions drastically reduced the amount of SHP-1 immunoprecipitated with KIR, suggesting that weak interactions with SHP-1 may be sufficient for inhibition.
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