insight - Computational Biology - # Allosteric Regulation of Plant Receptor Kinase Signaling

Allosteric Activation of the Co-Receptor BAK1 by the EFR Receptor Kinase Enables Immune Signaling in Plants

Q: How do the phosphorylation events on the EFR activation loop (S887/S888) and the conserved tyrosine (Y836) specifically regulate the conformational dynamics of the EFR kinase domain to enable allosteric activation of BAK1?

The phosphorylation events on the EFR activation loop (S887/S888) and the conserved tyrosine (Y836) play crucial roles in regulating the conformational dynamics of the EFR kinase domain to enable allosteric activation of BAK1. Phosphorylation of the activation loop residues (S887/S888) and the conserved tyrosine (Y836) are essential for switching the EFR kinase domain into an active-like conformation that can allosterically activate BAK1. The phosphorylation of these specific residues induces conformational changes in the EFR kinase domain, allowing it to adopt an active-like state that is necessary for its regulatory function in the signaling complex with BAK1. The phosphorylation events likely stabilize specific structural elements within the kinase domain, such as the A-loop and the VIa-Tyr residue, promoting the active conformation required for allosteric activation of BAK1.

Q: What are the structural details of the EFR-BAK1 kinase domain interface that mediate the allosteric activation mechanism, and how do they compare to allosteric regulation mechanisms observed in other kinase systems?

The structural details of the EFR-BAK1 kinase domain interface that mediate the allosteric activation mechanism involve specific interactions between the kinase domains of EFR and BAK1. The active conformation of the EFR kinase domain, stabilized by phosphorylation events, likely supports the positioning of the αC-helix in BAK1, which is crucial for its activation. This allosteric activation mechanism involves conformational changes in both EFR and BAK1 that are transmitted through the kinase domain interface, leading to enhanced catalytic activity of BAK1. The structural details of this interface may include key residues involved in stabilizing the active conformation, as well as potential allosteric communication pathways between the two kinase domains. Comparing this allosteric regulation mechanism to other kinase systems, similar principles of conformational dynamics and inter-domain communication are observed. In various kinase systems, allosteric regulation often involves conformational changes induced by post-translational modifications or ligand binding, leading to activation or inhibition of kinase activity. The EFR-BAK1 allosteric activation mechanism shares similarities with other kinase systems where conformational toggling and inter-domain interactions play critical roles in regulating kinase activity. Understanding the structural details of the EFR-BAK1 interface provides insights into the allosteric regulation of plant receptor kinase signaling pathways.

Q: Given the prevalence of pseudokinases in plant genomes, to what extent do non-catalytic signaling mechanisms like the one described for EFR-BAK1 operate across diverse plant receptor kinase pathways, and how might they have evolved to complement or replace canonical catalytic activation mechanisms?

Non-catalytic signaling mechanisms, such as the one described for EFR-BAK1, likely operate across diverse plant receptor kinase pathways, especially in systems where pseudokinases are prevalent. Pseudokinases are structurally similar to kinases but lack key catalytic residues, suggesting that they may function primarily through non-catalytic mechanisms. These non-catalytic signaling mechanisms are essential for regulating kinase activity, protein-protein interactions, and downstream signaling events in plant receptor kinase pathways. In diverse plant receptor kinase pathways, non-catalytic mechanisms may have evolved to complement or replace canonical catalytic activation mechanisms in several ways. First, non-catalytic mechanisms provide an additional layer of regulation and specificity in signaling pathways, allowing for fine-tuning of signaling responses. Second, they may enable rapid and reversible modulation of kinase activity without the need for catalytic turnover. Third, non-catalytic mechanisms can facilitate allosteric regulation and protein complex formation, enhancing the efficiency and specificity of signaling cascades. Overall, the evolution of non-catalytic signaling mechanisms in plant receptor kinase pathways reflects the complexity and adaptability of plant signaling networks, allowing for diverse regulatory strategies to coordinate cellular responses to environmental stimuli.

Core Concepts

The EFR receptor kinase allosterically activates the co-receptor kinase BAK1 to initiate immune signaling in plants, independent of EFR's own catalytic activity.

Abstract

The content describes a non-catalytic activation mechanism for the plant receptor kinase EFR (ELONGATION FACTOR TU RECEPTOR). Key insights:

EFR can allosterically activate the co-receptor kinase BAK1 to enhance its catalytic activity towards downstream substrates like BIK1, even when EFR itself is catalytically inactive.
Phosphorylation of the EFR activation loop (S887/S888) and a conserved tyrosine (Y836) in the kinase domain are crucial for EFR to adopt an active-like conformation that enables allosteric activation of BAK1.
Mutations that stabilize the active-like conformation of the EFR kinase domain, such as F761H, can partially restore the function of EFR variants that cannot be phosphorylated at the activation loop (EFRSSAA) or the conserved tyrosine (EFRY836F).
The allosteric activation mechanism appears to be conserved across the LRR-RK subfamily XIIa in Arabidopsis, where multiple members can signal independently of their own catalytic activity.
The active conformation of the EFR kinase domain is proposed to support the positioning of the αC-helix in BAK1, thereby allosterically activating BAK1 and enabling immune signaling.

Customize Summary

Rewrite with AI

Generate Citations

Translate Source

To Another Language

Generate MindMap

from source content

Visit Source

biorxiv.org

Stats

Rap addition increased BIK1D202N phosphorylation when the BRI1 or EFR kinase domains were dimerized with BAK1.
Kinase-dead EFRD849N retained some ability to enhance BIK1 phosphorylation, whereas kinase-dead BRI1D1009N failed to do so.
The EFRY836F mutation hampers the ability of the EFR kinase domain to adopt an active-like conformation.
The EFRF761H mutation partially restored the function of EFRY836F and EFRSSAA.

Quotes

"EFR is an active kinase, but a kinase-dead variant retains the ability to enhance catalytic activity of its co-receptor kinase BAK1/SERK3."
"Applying hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis and designing homology-based intragenic suppressor mutations, we provide evidence that the EFR kinase domain must adopt its active conformation in order to activate BAK1 allosterically, likely by supporting αC-helix positioning in BAK1."
"Our results suggest a conformational toggle model for signaling, in which BAK1 first phosphorylates EFR in the activation loop to stabilize its active conformation, allowing EFR in turn to allosterically activate BAK1."

Key Insights Distilled From

Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling

by Müh... at www.biorxiv.org 08-25-2023

https://www.biorxiv.org/content/10.1101/2023.08.23.554490v2

Deeper Inquiries

How do the phosphorylation events on the EFR activation loop (S887/S888) and the conserved tyrosine (Y836) specifically regulate the conformational dynamics of the EFR kinase domain to enable allosteric activation of BAK1?

The phosphorylation events on the EFR activation loop (S887/S888) and the conserved tyrosine (Y836) play crucial roles in regulating the conformational dynamics of the EFR kinase domain to enable allosteric activation of BAK1. Phosphorylation of the activation loop residues (S887/S888) and the conserved tyrosine (Y836) are essential for switching the EFR kinase domain into an active-like conformation that can allosterically activate BAK1. The phosphorylation of these specific residues induces conformational changes in the EFR kinase domain, allowing it to adopt an active-like state that is necessary for its regulatory function in the signaling complex with BAK1. The phosphorylation events likely stabilize specific structural elements within the kinase domain, such as the A-loop and the VIa-Tyr residue, promoting the active conformation required for allosteric activation of BAK1.

What are the structural details of the EFR-BAK1 kinase domain interface that mediate the allosteric activation mechanism, and how do they compare to allosteric regulation mechanisms observed in other kinase systems?

The structural details of the EFR-BAK1 kinase domain interface that mediate the allosteric activation mechanism involve specific interactions between the kinase domains of EFR and BAK1. The active conformation of the EFR kinase domain, stabilized by phosphorylation events, likely supports the positioning of the αC-helix in BAK1, which is crucial for its activation. This allosteric activation mechanism involves conformational changes in both EFR and BAK1 that are transmitted through the kinase domain interface, leading to enhanced catalytic activity of BAK1. The structural details of this interface may include key residues involved in stabilizing the active conformation, as well as potential allosteric communication pathways between the two kinase domains.
Comparing this allosteric regulation mechanism to other kinase systems, similar principles of conformational dynamics and inter-domain communication are observed. In various kinase systems, allosteric regulation often involves conformational changes induced by post-translational modifications or ligand binding, leading to activation or inhibition of kinase activity. The EFR-BAK1 allosteric activation mechanism shares similarities with other kinase systems where conformational toggling and inter-domain interactions play critical roles in regulating kinase activity. Understanding the structural details of the EFR-BAK1 interface provides insights into the allosteric regulation of plant receptor kinase signaling pathways.

Given the prevalence of pseudokinases in plant genomes, to what extent do non-catalytic signaling mechanisms like the one described for EFR-BAK1 operate across diverse plant receptor kinase pathways, and how might they have evolved to complement or replace canonical catalytic activation mechanisms?

Non-catalytic signaling mechanisms, such as the one described for EFR-BAK1, likely operate across diverse plant receptor kinase pathways, especially in systems where pseudokinases are prevalent. Pseudokinases are structurally similar to kinases but lack key catalytic residues, suggesting that they may function primarily through non-catalytic mechanisms. These non-catalytic signaling mechanisms are essential for regulating kinase activity, protein-protein interactions, and downstream signaling events in plant receptor kinase pathways.
In diverse plant receptor kinase pathways, non-catalytic mechanisms may have evolved to complement or replace canonical catalytic activation mechanisms in several ways. First, non-catalytic mechanisms provide an additional layer of regulation and specificity in signaling pathways, allowing for fine-tuning of signaling responses. Second, they may enable rapid and reversible modulation of kinase activity without the need for catalytic turnover. Third, non-catalytic mechanisms can facilitate allosteric regulation and protein complex formation, enhancing the efficiency and specificity of signaling cascades. Overall, the evolution of non-catalytic signaling mechanisms in plant receptor kinase pathways reflects the complexity and adaptability of plant signaling networks, allowing for diverse regulatory strategies to coordinate cellular responses to environmental stimuli.