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

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Madhuprakash, Jogi, Toghani, Amir Ali, Contreras, Mauricio P., Posbeyikian, Andres, Richardson, Jake, Kourelis, Jiorgos, Bozkurt, Tolga O., Webster, Michael W. and Kamoun, Sophien (2024) A disease resistance protein triggers oligomerization of its NLR helper into a hexameric resistosome to mediate innate immunity. Science Advances, 10 (45). ISSN 2375-2548

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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.

Item Type: Article
Additional Information: Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Data related to the NbNRC2 hexamer structure can be found at PDB/EMDB, with PDB ID 9FP6 and EMDB ID EMD-50637, as well as in table S1. Datasets associated to AlphaFold 3 NLR oligomer predictions can be accessed on Zenodo [ref. 50]. All scripts used to extract information from AlphaFold predicted structures are available at github.com/amiralito/NRC2Hexamer [ref. 49]. Funding Information: The Gatsby charitable foundation, Biotechnology and Biological Sciences Research Council (BBSRC) BB/P012574 (Plant Health ISP), BBSRC BBS/E/J/000PR9795, BBSRC BBS/E/J/000PR9796 (Plant Health ISP–Response), BBSRC BBS/E/J/000PR9797 (Plant Health ISP–Susceptibility), BBSRC BBS/E/J/000PR9798 (Plant Health ISP–Evolution), BBSRC BB/V002937/1, BBSRC BB/X016382/1, BBSRC BB/T006102/1, and BBSRC BB/X01102X/1; the European Research Council (ERC) 743165; and UK Research and Innovation (UKRI) Future Leaders Fellowship MR/X033481/1. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Uncontrolled Keywords: general ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School: Faculty of Science > The Sainsbury Laboratory
Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Science > Research Groups > Plant Sciences
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Depositing User: LivePure Connector
Date Deposited: 16 Jan 2025 01:09
Last Modified: 28 Jan 2025 23:48
URI: https://ueaeprints.uea.ac.uk/id/eprint/98217
DOI:

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