A disease resistance protein triggers oligomerization of its NLR helper into a hexameric resistosome to mediate innate immunity

Jogi Madhuprakash, Amir Ali Toghani, Mauricio P. Contreras, Andres Posbeyikian, Jake Richardson, Jiorgos Kourelis, Tolga O. Bozkurt, Michael W. Webster, Sophien Kamoun

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Abstract

NRCs are essential helper NLR (nucleotide-binding domain and leucine-rich repeat) proteins that execute immune responses triggered by sensor NLRs. The resting state of NbNRC2 was recently shown to be a homodimer, but the sensor-activated state remains unclear. Using cryo-EM, we determined the structure of sensor-activated NbNRC2, which forms a hexameric inflammasome-like resistosome. Mutagenesis of the oligomerization interface abolished immune signaling, confirming the functional significance of the NbNRC2 resistosome. Comparative structural analyses between the resting state homodimer and sensor-activated homohexamer revealed substantial rearrangements, providing insights into NLR activation mechanisms. Furthermore, structural comparisons between NbNRC2 hexamer and previously reported CC-NLR pentameric assemblies revealed features allowing an additional protomer integration. Using the NbNRC2 hexamer structure, we assessed the recently released AlphaFold 3 for predicting activated CC-NLR oligomers, revealing high-confidence modeling of NbNRC2 and other CC-NLR amino-terminal α1 helices, a region proven difficult to resolve structurally. Overall, our work sheds light on NLR activation mechanisms and expands understanding of NLR structural diversity.

Original languageEnglish
Article numbereadr2594
JournalScience Advances
Volume10
Issue number45
DOIs
Publication statusPublished - 8 Nov 2024

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