A family of human receptors structurally related to Drosophila Toll

The discovery of sequence homology between the cytoplasmic domains of Drosophila Toll and human inter- leukin 1 receptors has sown the conviction that both molecules trigger related signaling pathways tied to the nuclear trans- location 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 re- ceptors—named TLRs 1-5—are probably the direct homologs of the f ly 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 dorsoventral- ization of the Drosophila embryo—as regulators of early morphogenetic patterning. Multiple tissue mRNA blots indi- cate markedly different patterns of expression for the human TLRs. By using f luorescence in situ hybridization and se- quence-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 bya 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.