Nucleotide binding, leucine-rich repeat (NB-LRR) proteins constitute a major component of plant resistance to infection by pathogens. While the mechanisms through which NB-LRR proteins are able to perceive pathogen invasion are becoming increasingly well understood, the means by which these proteins are able to translate pathogen detection into the induction of a conserved resistance response in the plant remains uncertain. N-terminal domains have long been assumed to function in NBLRR protein signal initiation, though only limited evidence exists in support of this hypothesis. Here, we report that the NB domain, rather than the N-terminal CC (coiled-coil) domain of the potato (Solanum tuberosum) NB-LRR protein Rx is sufficient for the induction of defense responses, suggesting that the point of Rx signal initiation resides within the NB domain. We have identified regions of the Rx CC domain central to mediating its interaction with the hypothesized Rx recognition co-factor RanGAP2, and regions of the Rx NB domain which are critical for signal initiation. We further report the capability of the Rx and other NB domains to oligomerize, both homotypically and heterotypically. Among NB-LRR proteins able to participate in NB - NB heterotypic oligomerization are members of the CCR-NB-LRR clade of NB-LRR proteins. We herein present the characterization of this unique and highly conserved class of NB-LRR protein, distinguished by having CC domains most closely ! resembling the Arabidopsis RPW8 protein. We have found that the CCR domain is independently capable of defense response induction, setting CCR-NB-LRR proteins apart from canonical CC-NB-LRR proteins functionally as well as phylogenetically. We additionally report the striking correlation between the occurrence of NRG1-like CCR-NB-LRR-encoding genes and TIR- (Toll and Interleukin-1 receptor homology) NB-LRR-encoding genes across the genomes of both monocotyledonous and dicotyledonous plant species. Taken together, the findings presented here suggest a functional correlation between CCR-NB-LRR proteins and canonical NB-LRR proteins, with NB-mediated oligomerization presenting one possible means of realizing this relationship. !