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Cell Rep. 2016 Nov 15;17(8):1907-1914. doi: 10.1016/j.celrep.2016.10.067.

Structural Basis for the Activation of IKK1/α.

Author information

1
Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093, USA; Laboratory of Genetics and Helmsley Center for Genomic Medicine, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
2
Laboratory of Genetics and Helmsley Center for Genomic Medicine, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
3
Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.
4
Laboratory of Genetics and Helmsley Center for Genomic Medicine, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: dlyumkis@salk.edu.
5
Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: gghosh@ucsd.edu.

Abstract

Distinct signaling pathways activate the NF-κB family of transcription factors. The canonical NF-κB-signaling pathway is mediated by IκB kinase 2/β (IKK2/β), while the non-canonical pathway depends on IKK1/α. 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-κB 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.

PMID:
27851956
PMCID:
PMC5508515
DOI:
10.1016/j.celrep.2016.10.067
[Indexed for MEDLINE]
Free PMC Article

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