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

ABSTRACT: Rapid and high-fidelity phosphorylation of serine residues at positions 32 and 36 of IκBα by IKK2/β, a highly conserved prototypical Ser/Thr kinase in vertebrates, is critical for canonical NF-κB activation. Here, we report that human IKK2 not only phosphorylates substrate serine residues and autophosphorylates its own activation loop, but also autophosphorylates at a tyrosine residue proximal to the active site and is, therefore, a dual-specificity kinase. We observed that mutation of Y169, an autophosphorylatable tyrosine located at the DFG +1 (DLG in IKK1/α and 2) position, to phenylalanine renders IKK2 incapable of catalyzing phosphorylation at S32 within its IκBα substrate. We also observed that mutation of the phylogenetically conserved ATP-contacting residue K44 in IKK2 to methionin

SUBMITTER: Borar P 

PROVIDER: S-EPMC12208667 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature