Structural Insights into the Autoinhibition and Cofactor Binding of a Plant Immune Receptor NLR Protein

Core Concepts

Plant NLR proteins maintain a balanced immune response through oligomerization-mediated autoinhibition and binding of inositol phosphates as cofactors.

Abstract

The article investigates the mechanisms underlying the autoinhibition and activation of the plant NLR (nucleotide-binding leucine-rich repeat) protein NRC2, which belongs to a small group of NLRs characterized by constitutively high expression without self-activation.
Key insights:

The tomato NRC2 (SlNRC2) protein forms dimers, tetramers, and higher-order oligomers, with the oligomeric states stabilizing the inactive conformation and sequestering SlNRC2 from assembling into an active form.
Cryo-electron microscopy (cryo-EM) structures reveal that the inner surface of SlNRC2's C-terminal LRR domain binds to inositol hexakisphosphate (IP6) or pentakisphosphate (IP5), as confirmed by mass spectrometry.
Mutations at the dimeric or inter-dimeric interfaces, as well as the IP-binding site, enhance pathogen-induced cell death and immunity in Nicotiana benthamiana, suggesting that oligomerization and inositol phosphate binding play a crucial role in the negative regulation of NLR activation.
The study unveils a novel negative regulatory mechanism of NLR activation and identifies inositol phosphates as potential cofactors of NRC proteins, providing important structural and functional insights into plant immune receptor regulation.

Stats

SlNRC2 forms dimers, tetramers, and higher-order oligomers.
Cryo-EM structures reveal inositol hexakisphosphate (IP6) or pentakisphosphate (IP5) bound to the inner surface of SlNRC2's C-terminal LRR domain.
Mutations at the dimeric or inter-dimeric interfaces, as well as the IP-binding site, enhance pathogen-induced cell death and immunity in Nicotiana benthamiana.

Quotes

"Maintaining a balanced immune response is crucial, as excessive NLR expression can lead to unintended autoimmunity."
"Dimerization and oligomerization not only stabilize the inactive state but also sequester SlNRC2 from assembling into an active form."
"Mutations at the IP-binding site impair inositol phosphate binding of SlNRC2 and pathogen-induced SlNRC2-mediated cell death in N. benthamiana."

Key Insights Distilled From

Oligomerization-mediated autoinhibition and cofactor binding of a plant NLR - Nature

by Shoucai Ma,C... at www.nature.com 06-12-2024

https://www.nature.com/articles/s41586-024-07668-7

Deeper Inquiries

How do the oligomeric states and inositol phosphate binding of NRC2 proteins regulate their interactions with other immune signaling components?

The oligomeric states of NRC2 proteins play a crucial role in regulating their interactions with other immune signaling components. The formation of dimers and tetramers, as well as higher-order oligomers, stabilizes the inactive conformation of NRC2, preventing it from assembling into an active form. This autoinhibitory mechanism ensures that NRC2 is not constitutively active, thereby preventing unintended autoimmunity. Additionally, the oligomerization of NRC2 sequesters it from interacting with other immune signaling components, thus maintaining a balanced immune response. Furthermore, the binding of inositol hexakisphosphate (IP6) or pentakisphosphate (IP5) to the inner surface of SlNRC2's C-terminal LRR domain also regulates its interactions with immune signaling components. Mutations at the IP-binding site impair inositol phosphate binding of SlNRC2, affecting its ability to mediate cell death and immunity in plants.

What are the potential evolutionary advantages of the autoinhibitory mechanisms observed in plant NLR proteins compared to other immune receptor systems?

The autoinhibitory mechanisms observed in plant NLR proteins, such as NRC2, offer several potential evolutionary advantages compared to other immune receptor systems. Firstly, these mechanisms prevent the constitutive activation of NLR proteins, which could lead to unintended autoimmunity and detrimental effects on plant fitness. By maintaining NLR proteins in an inactive state until pathogen recognition occurs, plants can avoid unnecessary immune responses and allocate resources more efficiently. Additionally, the oligomerization-mediated autoinhibition of NRC2 provides a tight regulatory control over its activation, ensuring a balanced immune response. This precise regulation allows plants to fine-tune their immune responses based on the specific pathogen encountered, enhancing their ability to adapt to diverse environmental challenges. Overall, the autoinhibitory mechanisms in plant NLR proteins represent an evolutionary strategy to optimize immune responses while minimizing potential fitness costs.

Could the insights from this study on NRC2 regulation be applied to engineer more robust and balanced immune responses in crop plants against diverse pathogens?

The insights gained from the study on NRC2 regulation hold significant potential for engineering more robust and balanced immune responses in crop plants against diverse pathogens. By understanding the mechanisms underlying NRC2 autoinhibition and activation, researchers can potentially manipulate these processes to enhance plant immunity. For instance, targeted mutations at the dimeric or inter-dimeric interfaces of NRC2 could be introduced to enhance pathogen-induced cell death and immunity in crop plants. Similarly, modulating the inositol phosphate binding site of NRC2 could be explored as a strategy to fine-tune immune responses in crops. By leveraging the negative regulatory mechanisms of NLR activation uncovered in this study, it may be possible to develop crop plants with improved resistance to a wide range of pathogens while maintaining a balanced immune response. This approach could contribute to sustainable agriculture practices by reducing the reliance on chemical pesticides and enhancing crop resilience in the face of evolving pathogen populations.