Structural Basis for the Activation of IKK1/?.

ABSTRACT: Distinct signaling pathways activate the NF-?B family of transcription factors. The canonical NF-?B-signaling pathway is mediated by I?B kinase 2/? (IKK2/?), while the non-canonical pathway depends on IKK1/?. 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 (?150 kDa) and hexameric (?450 kDa) forms. The hexamer, which is the representative form in the crystal but comprises only ?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-?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.

SUBMITTER: Polley S 

PROVIDER: S-EPMC5508515 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature