
IKK2キナーゼは、自身のチロシン残基をリン酸化することで、IκBαのセリン32/36を特異的にリン酸化することができる。この自己リン酸化機構が、NF-κBシグナル伝達の高い忠実性を保証している。


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Rapid and high-fidelity phosphorylation of two serines (S32 and S36) of IκBα by a prototype Ser/Thr kinase IKK2 is critical for fruitful canonical NF-κB activation. Here, we report that IKK2 is a dual specificity Ser/Thr kinase that autophosphorylates itself at tyrosine residues in addition to its activation loop serines. Mutation of one such tyrosine, Y169, located in proximity to the active site, to phenylalanine, renders IKK2 inactive for phosphorylation of S32 of IκBα. Surprisingly, auto-phosphorylated IKK2 relayed phosphate group(s) to IκBα without ATP when ADP is present. We also observed that mutation of K44, an ATP-binding lysine conserved in all protein kinases, to methionine renders IKK2 inactive towards specific phosphorylation of S32 or S36 of IκBα, but not non-specific substrates. These observations highlight an unusual evolution of IKK2, in which autophosphorylation of tyrosine(s) in the activation loop and the invariant ATP-binding K44 residue define its signal-responsive substrate specificity ensuring the fidelity of NF-κB activation.

### Competing Interest Statement

The authors have declared no competing interest.

Dual-specific autophosphorylation of kinase IKK2 enables phosphorylation of substrate IκBα through a phosphoenzyme intermediate

ikk2キナーゼの独特な自己リン酸化機構が-iκbαの特異的リン酸化を可能にする


IKK2キナーゼの独特な自己リン酸化機構が、IκBαの特異的リン酸化を可能にする


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EFR受容体キナーゼは、自身の触媒活性を必要とせずに、BAK1共受容体キナーゼを非触媒的に活性化することで免疫シグナル伝達を促進する。


Transmembrane signaling by plant receptor kinases (RKs) has long been thought to involve reciprocal trans-phosphorylation of their intracellular kinase domains. The fact that many of these are pseudokinase domains, however, suggests that additional mechanisms must govern RK signaling activation. Non-catalytic signaling mechanisms of protein kinase domainshave been described in metazoans, but information is scarce for plants. Recently, a non-catalytic function was reported for the leucine-rich repeat (LRR)-RK subfamily XIIa member EFR (ELONGATION FACTOR TU RECEPTOR) and phosphorylation-dependent conformational changes were proposed to regulate signaling of RKs with non-RD kinase domains. Here, using EFR as a model, we describe a non-catalytic activation mechanism for LRR-RKs with non-RD kinase domains. EFR is an active kinase, but a kinase-dead variant retains the ability to enhance catalytic activity of its co-receptor kinase BAK1/SERK3 (BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3). 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.

### Competing Interest Statement

The authors have declared no competing interest.

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

病原体関連分子パターンを認識するefr受容体キナーゼによるbak1共受容体の非触媒的な活性化機構


病原体関連分子パターンを認識するEFR受容体キナーゼによるBAK1共受容体の非触媒的な活性化機構
