Figure 24–3 A scanning electron micrograph of a mutant fruit fly that died from a fungal infection. The fly is covered with fungal hyphae, as it lacked a Toll receptor, which helps protect Drosophila from fungal infections. (From B. Lemaitre  et al., Cell 86:973–983, 1996.) the membranes of the endolysosomal system (discussed in Chapter 13). Still other PRRs are secreted and bind to the surface of extracellular pathogens, marking them for destruction by either phagocytes or blood proteins that are part of the complement system (discussed later).
There Are Multiple classes of prrs
The first PRR identified was the Toll receptor in Drosophila, which was well-known for its role in fly development (see Figure 21–17). It was later discovered to be also required for the production of antimicrobial peptides that protect the fly against fungal infections (Figure 24–3). Toll is a transmembrane glycoprotein with a large extracellular domain that contains a series of leucine-rich repeats. Soon it was discovered that both plants and animals have a variety of Toll-like receptors (TLRs) that function as PRRs in innate immune responses against various pathogens. Mammals make at least 10 different TLRs, each recognizing distinct ligands: TLR3, for example, recognizes double-stranded viral RNA in the endosomal lumen (Figure 24–4); TLR4 recognizes lipopolysaccharide (LPS) on the outer
Figure 24–4 A Toll-like receptor. The structure of human TLr3 is shown (green), with a double-stranded rNA molecule (dsrNA, blue) bound to it. The receptor is a homodimer in the membrane of endosomes. The binding of dsrNA to the two horseshoe-shaped domains on the lumenal endosome membrane side of the endosome brings the two cytosolic domains together, allowing adaptor proteins in the cytosol to assemble into a large signaling complex (not shown). (B) The crystal structure of a lumenal domain of the receptor, which contains 23 conventional leucine-rich repeats, each of which contributes a β strand to the continuous β sheet (red) that lines the concave surface of the structure. (A, adapted from L. Liu et al., Science 320:379–381, 2008. With permission from AAAS; B, adapted from J. choe, M.S. Kelker and I.A. Wilson, Science 309:581–585, 2006; pDB: 1ZIW.) 0.2 mm membrane of Gram-negative bacteria; TLR5 recognizes the protein that forms the bacterial flagellum; and TLR9 recognizes short, unmethylated sequences of bacterial, viral, or protozoan DNA, called CpG motifs, which are uncommon in vertebrate DNA.