Structural Basis for the Activation of IKK1/α

Distinct signaling pathways activate the NF-kappa B family of transcription factors. The canonical NF-kappa B-signaling pathway is mediated by I kappa B kinase 2/beta (IKK2/beta), while the non-canonical pathway depends on IKK1/alpha. The structural and biochemical bases for distinct signaling by these otherwise highly similar IKKs are unclear. We report single-particle cryoelectron microscopy (cryo-EM) and X-ray crystal structures of human IKK1 in dimeric (similar to 150 kDa) and hexameric (similar to 450 kDa) forms. The hexamer, which is the representative form in the crystal but comprises only similar to 2% of the particles in solution by cryo-EM, is a trimer of IKK1 dimers. While IKK1 hexamers are not detectable in cells, the surface that supports hexamer formation is critical for IKK1-dependent cellular processing of p100 to p52, the hallmark of non-canonical NF-kappa B signaling. Comparison of this surface to that in IKK2 indicates significant divergence, and it suggests a fundamental role for this surface in signaling by these kinases through distinct pathways.