J. Biol. Chem., Vol. 267, Issue 4, 2605-2609, 02, 1992
Amino acids conserved in interleukin-1 receptors (IL-1Rs) and the Drosophila toll protein are essential for IL-1R signal transduction
A Heguy, CT Baldari, G Macchia, JL Telford and M Melli
Sclavo Research Center, Siena, Italy.
The cytoplasmic domain of the human T cell-type interleukin-1 receptor
(hIL-1R) is not involved in the binding, internalization, or nuclear
localization of interleukin-1 (IL-1), but is essential for signal
transduction. We have previously localized a 50-amino acid region (residues
477-527) critical for IL-1-mediated activation of the interleukin-2
promoter in T cells. This region displays a striking degree of amino acid
conservation in human, murine, and chicken IL-1Rs. Here we report the
results of a site-directed mutational analysis of the cytoplasmic domain of
the hIL-1R. We have introduced single-amino acid substitutions at positions
conserved in all three receptors and at nonconserved positions and
identified key amino acids for IL-1R function in signal transduction. Three
basic (Arg431, Lys515, and Arg518) and 3 aromatic (Phe513, Trp514, and
Tyr519) amino acids that are conserved in human, murine, and chicken IL-1Rs
could not be replaced without abolishing IL-1R-mediated signal
transduction. A substitution at another conserved position (Pro521) reduces
significantly the ability of the IL-1R to transmit the IL-1 signal.
Nonconserved residues could be replaced without affecting signal
transduction. The cytoplasmic domain of the IL-1R is related to that of the
Drosophila Toll protein, with a 26% identity and a 43% similarity in amino
acid sequence. The amino acids shown to be essential for IL-1R function are
conserved in the Toll protein. Our experimental data indicate that the
amino acid sequence similarity between the IL-1R and the Drosophila toll
protein reflects a functional homology between the two proteins.
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