A family of human receptors structurally related to Drosophila Toll

FL Rock, G Hardiman, JC Timans… - Proceedings of the …, 1998 - National Acad Sciences
FL Rock, G Hardiman, JC Timans, RA Kastelein, JF Bazan
Proceedings of the National Academy of Sciences, 1998National Acad Sciences
The discovery of sequence homology between the cytoplasmic domains of Drosophila Toll
and human interleukin 1 receptors has sown the conviction that both molecules trigger
related signaling pathways tied to the nuclear translocation of Rel-type transcription factors.
This conserved signaling scheme governs an evolutionarily ancient immune response in
both insects and vertebrates. We report the molecular cloning of a class of putative human
receptors with a protein architecture that is similar to Drosophila Toll in both intra-and …
The discovery of sequence homology between the cytoplasmic domains of Drosophila Toll and human interleukin 1 receptors has sown the conviction that both molecules trigger related signaling pathways tied to the nuclear translocation of Rel-type transcription factors. This conserved signaling scheme governs an evolutionarily ancient immune response in both insects and vertebrates. We report the molecular cloning of a class of putative human receptors with a protein architecture that is similar to Drosophila Toll in both intra- and extracellular segments. Five human Toll-like receptors—named TLRs 1–5—are probably the direct homologs of the fly molecule and, as such, could constitute an important and unrecognized component of innate immunity in humans. Intriguingly, the evolutionary retention of TLRs in vertebrates may indicate another role—akin to Toll in the dorsoventralization of the Drosophila embryo—as regulators of early morphogenetic patterning. Multiple tissue mRNA blots indicate markedly different patterns of expression for the human TLRs. By using fluorescence in situ hybridization and sequence-tagged site database analyses, we also show that the cognate Tlr genes reside on chromosomes 4 (TLRs 1, 2, and 3), 9 (TLR4), and 1 (TLR5). Structure prediction of the aligned Toll-homology domains from varied insect and human TLRs, vertebrate interleukin 1 receptors and MyD88 factors, and plant disease-resistance proteins recognizes a parallel β/α fold with an acidic active site; a similar structure notably recurs in a class of response regulators broadly involved in transducing sensory information in bacteria.
National Acad Sciences