title: Structural Basis for the Activation of IKK1/α.
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.
authors.affiliation: 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.
authors.forename: Smarajit
authors.initials: S
authors.lastname: Polley
authors.affiliation: Laboratory of Genetics and Helmsley Center for Genomic Medicine, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Dario Oliveira
authors.initials: DO
authors.lastname: Passos
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: De-Bin
authors.initials: DB
authors.lastname: Huang
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Mulero
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Anup
authors.initials: A
authors.lastname: Mazumder
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Tapan
authors.initials: T
authors.lastname: Biswas
authors.affiliation: Laboratory of Genetics and Helmsley Center for Genomic Medicine, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
authors.affiliation: 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.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lyumkis
authors.affiliation: Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: gghosh@ucsd.edu.
authors.forename: Gourisankar
authors.initials: G
authors.lastname: Ghosh
mesh_terms: D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D055503:Protein Multimerization; D013329:Structure-Activity Relationship
chemical_list: D050505:Mutant Proteins; D016328:NF-kappa B; D051550:I-kappa B Kinase