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Fig. 1. Tomato Cf proteins and structurally related proteins. (A) Cf proteins contain different numbers of N-terminal eLRRs, a transmembrane (TM) domain, and a short cytoplasmic domain (CD). (B) Rice Xa-21 and tomato Pto bacterial R proteins. (C) eLRR-TM domain-containing proteins with different cytoplasmic domains (CD). See text for descriptions.

Both the Cf class and Xa21 resemble the Drosophila Toll receptor and its human homologs, the Toll-like receptors (TLRs) (18). TLR2 and TLR4 (Fig. 1C) function in innate immunity and activate microbial defense pathways to trigger inflammatory responses after recognition of conserved molecular structures of distinct microbial pathogen classes (19). TLRs have therefore been designated “pattern recognition receptors” (20) and serve an analogous role to plant R proteins in detecting pathogen molecules and activating defense pathways. Interestingly, TLR-mediated inflammatory responses resemble plant defense responses, including production of antimicrobial active oxygen species and nitric oxide and ultimately cell death (21, 22). The significance of these homologies for plant R protein mechanisms has yet to be established, but it is tempting to suggest that, whereas vertebrates use the TLRs to recognize conserved structures of different pathogen classes, plants have evolved these to detect strain-specific pathogen Avr products.

Arabidopsis RPP1 and RPP5 genes confer resistance to P. parasitica and belong to the largest class of R genes that encode nucleotide-binding leucine-rich repeat (NB-LRR) proteins (Fig. 2A). Genome sequencing has shown that approximately 200 NB-LRR-encoding genes are present in Arabidopsis (23). NBLRR proteins can be divided into two subclasses on the basis of their N-terminal domain. The leucine zipper (LZ)-NB-LRR is a broad class of NB-LRR proteins (with perhaps two subclasses) that contains an N-terminal putative heptad LZ or coiled-coil domain (23). Members of this class have been identified for resistance to bacteria, viruses, fungi, oomycetes, and even nematodes and aphids. Examples include Arabidopsis RPS2, RPM1, and RPS5 for resistance to P. syringae (24), RPP8 for resistance to P. parasitica (25), and maize Rp1 for resistance to Puccinia sorghi (26).

Members of the TIR-NB-LRR class carry N-terminal homology with the cytoplasmic domain of the Toll and interkeukin-1 receptors (Fig. 2B) involved in vertebrate innate immunity (27, 28). Besides RPP1 and RPP5, this class also includes tobacco N for resistance to tobacco mosaic virus, flax L6 for resistance to flax rust, and Arabidopsis RPS4 for resistance to P. syringae (24, 29). After activation, the TIR domain of human TLR2 and TLR4 binds, through homophilic interactions, to the TIR domain of the MyD88 adaptor protein (Fig. 2B) (30). MyD88 also carries a death domain (DD) that then binds to the DD of the Ser/Thr protein kinase IRAK (the human ortholog of Drosophila Pelle, and interestingly, also homologous to tomato Pto; Fig. 1B), leading to the translocation of the transcription factor NF-κB and induction of the inflammatory response (27). These homologies may suggest a role for the TIR domain of the plant R proteins in homophilic TIR–TIR interactions with TIR domaincontaining plant adaptor proteins, but these have yet to be reported in plants.

Fig. 2. Arabidopsis RPP1, RPP5, and structurally related proteins. (A) RPP1 and RPP5 have an N-terminal TIR domain, a nucleotide-binding Apaf-1, R proteins and CED4 homology (NB-ARC) domain, and a LRR domain. The RPP1 family differ by their N-terminal domains, which are absent in RPP5: RPP1A has a putative signal anchor (SA) domain, RPP1B,C have hydrophobic domains (HD). (B) Human proteins that function in the NF-κB pathway. eLRR, extracellular LRR domain; TM, transmembrane domain. (C) Human proteins with CARDs that function in NF-κB and/or apoptosis pathways. See text for descriptions.

An intriguing homology has been noted between plant NB-LRR proteins and the apoptotic adaptor CED4 from Caenorhabditis elegans (31). This region of homology also extends to its human ortholog Apaf-1 (Fig. 2C) (32) and has been designated the NB-ARC domain (Fig. 2C) (33) or Ap-ATPase domain (34). The NB-ARC domain is an ancient motif, because it is also present in proteins of Gram-positive bacteria (34). Another protein that resembles plant NB-LRR proteins is human caspase recruitment domain (CARD)4/Nod1 (35, 36), which contains LRRs and a NB site (the homology to the rest of the NB-ARC domain is less convincing). Instead of TIR or LZ domains at their N termini, Apaf-1 and CARD4/Nod1 carry CARDs (Fig. 2C). Induction of apoptosis by both Apaf-1 and CARD4/Nod1 occurs through homophilic CARD–CARD interactions with caspase-9, a CARD-containing cysteine protease (36, 37). CARD4/Nod1, in addition, plays a role in activation of the NF-κB pathway through homophilic CARD–CARD interactions with the Ser/Thr kinase RICK (Fig. 2C) (35, 36). Caspases and CARDs have not yet been reported in plants; however, the use of peptide inhibitors specific to caspases in animal cells suggests plants may possess caspase activity (38). Although the significance of these homologies is not clear, they provide interesting paradigms for NB-LRR protein mechanisms. For example, the WD40 repeat domain of Apaf-1 negatively regulates its NBARC domain, which is alleviated after binding to cytochrome c, then allowing ATP-dependent oligomerization and caspase-9 activation (37). By analogy, pathogen Avr signals perceived by the LRR domain of plant NB-LRR proteins might alleviate negative regulation of their NB-ARC domain such that ATP hydrolysis and oligomerization can be initiated, possibly leading to homo- or heterodimerization (through



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