The IκB kinase (IkappaB kinase or IKK) is an enzyme complex that is involved in propagating the cellular response to inflammation, specifically the regulation of lymphocytes.
The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade. The IκBα (inhibitor of nuclear factor kappa B) protein inactivates the NF-κB transcription factor by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm. Specifically, IKK phosphorylates the inhibitory IκBα protein. This phosphorylation results in the dissociation of IκBα from NF-κB. NF-κB, which is now free, migrates into the nucleus and activates the expression of at least 150 genes; some of which are anti-apoptotic.
Catalyzed reaction
In enzymology, an IκB kinase () is an enzyme that catalyzes the chemical reaction:
ATP + IκB protein ADP + IκB phosphoprotein
Thus, the two substrates of this enzyme are ATP and IκB protein, whereas its two products are ADP and IκB phosphoprotein.
This enzyme belongs to the family of transferases, specifically those transferring a phosphate group to the sidechain oxygen atom of serine or threonine residues in proteins (protein-serine/threonine kinases). The systematic name of this enzyme class is ATP:[IκB protein] phosphotransferase.
Structure
The IκB kinase complex is composed of three subunits each encoded by a separate gene: IKK-α (also known as IKK1) () IKK-β (also known as IKK2) () IKK-γ (also known as NEMO) () The α- and β-subunits together are catalytically active whereas the γ-subunit serves a regulatory function.
The IKK-α and IKK-β kinase subunits are homologous in structure, composed of a kinase domain, as well as leucine zipper and helix-loop-helix dimerization domains, and a carboxy-terminal NEMO-binding domain (NBD). Mutational studies have revealed the identity of the NBD amino acid sequence as leucine-aspartate-tryptophan-serine-tryptophan-leucine, encoded by residues 737-742 and 738-743 of IKK-α and IKK-β, respectively. The regulatory IKK-γ subunit, or NEMO, is composed of two coiled coil domains, a leucine zipper dimerization domain, and a zinc finger-binding domain. Specifically, the NH2-terminus of NEMO binds to the NBD sequences on IKK-α and IKK-β, leaving the rest of NEMO accessible for interacting with regulatory proteins.
Function
IκB kinase activity is essential for activation of members of the nuclear factor-kB (NF-κB) family of transcription factors, which play a fundamental role in lymphocyte immunoregulation. Activation of the canonical, or classical, NF-κB pathway begins in response to stimulation by various pro-inflammatory stimuli, including lipopolysaccharide (LPS) expressed on the surface of pathogens, or the release of pro-inflammatory cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1). Following immune cell stimulation, a signal transduction cascade leads to the activation of the IKK complex, an event characterized by the binding of NEMO to the homologous kinase subunits IKK-α and IKK-β. The IKK complex phosphorylates serine residues (S32 and S36) within the amino-terminal domain of inhibitor of NF-κB (IκBα) upon activation, consequently leading to its ubiquitination and subsequent degradation by the proteasome. Degradation of IκBα releases the prototypical p50-p65 dimer for translocation to the nucleus, where it binds to κB sites and directs NF-κB-dependent transcriptional activity. NF-κB target genes can be differentiated by their different functional roles within lymphocyte immunoregulation and include positive cell-cycle regulators, anti-apoptotic and survival factors, and pro-inflammatory genes. Collectively, activation of these immunoregulatory factors promotes lymphocyte proliferation, differentiation, growth, and survival.