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Structural Basis for the Activation of IKK1/α.

<div class='caption-title'>(A) Domain organization is as follows: KD, kinase domain; ULD, ubiquitin-like domain; SDD, scaffold dimerization domain; and NBD, NEMO-binding domain. Functionally relevant residues and those mutated in this study are marked.</div>
<div class='caption-title'>(A) Atomic models of three different conformers superimposed on a transparent isosurface representation of their respective cryo-EM maps are shown.</div>
<div class='caption-title'>(A) Size-exclusion profiles of overexpressed IKK1 (WT and HY mutant) and IKK2 in S100 extracts of 293T cells. Protein levels are assessed by western blot and normalized band intensities are plotted.</div>
Polley S, Passos DO, Huang DB, Mulero MC, Mazumder A, Biswas T, Verma IM, Lyumkis D, Ghosh G
OpenAccess logo Cell Rep 17 1907-1914 (2016)
Related entries: 5ebz, 5tqw, 5tqx

Cited: 29 times
EuropePMC logo PMID: 27851956

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.

Articles - 5tqy mentioned but not cited (6)

  1. Structural Basis for the Activation of IKK1/α. Polley S, Passos DO, Huang DB, Mulero MC, Mazumder A, Biswas T, Verma IM, Lyumkis D, Ghosh G. Cell Rep 17 1907-1914 (2016)
  2. Chrysin Inhibits NF-κB-Dependent CCL5 Transcription by Targeting IκB Kinase in the Atopic Dermatitis-Like Inflammatory Microenvironment. Yeo H, Lee YH, Koh D, Lim Y, Shin SY. Int J Mol Sci 21 E7348 (2020)
  3. Isodeoxyelephantopin, a Sesquiterpene Lactone Induces ROS Generation, Suppresses NF-κB Activation, Modulates LncRNA Expression and Exhibit Activities Against Breast Cancer. Verma SS, Rai V, Awasthee N, Dhasmana A, Rajalaksmi DS, Nair MS, Gupta SC. Sci Rep 9 17980 (2019)
  4. MAINMASTseg: Automated Map Segmentation Method for Cryo-EM Density Maps with Symmetry. Terashi G, Kagaya Y, Kihara D. J Chem Inf Model 60 2634-2643 (2020)
  5. Biochemical and Computational Studies of the Interaction between a Glucosamine Derivative, NAPA, and the IKKα Kinase. Lopreiato M, Di Cristofano S, Cocchiola R, Mariano A, Guerrizio L, Scandurra R, Mosca L, Raimondo D, Scotto d'Abusco A. Int J Mol Sci 22 1643 (2021)
  6. Comprehensive Assessment of Indian Variations in the Druggable Kinome Landscape Highlights Distinct Insights at the Sequence, Structure and Pharmacogenomic Stratum. Panda G, Mishra N, Sharma D, Kutum R, Bhoyar RC, Jain A, Imran M, Senthilvel V, Divakar MK, Mishra A, Garg P, Banerjee P, Sivasubbu S, Scaria V, Ray A. Front Pharmacol 13 858345 (2022)


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  1. Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors. Prescott JA, Cook SJ. Cells 7 E115 (2018)
  2. NFκB and Kidney Injury. Song N, Thaiss F, Guo L. Front Immunol 10 815 (2019)
  3. The NF-κB Activating Pathways in Multiple Myeloma. Roy P, Sarkar UA, Basak S. Biomedicines 6 E59 (2018)
  4. Noncanonical NF-κB in Cancer. Tegowski M, Baldwin A. Biomedicines 6 E66 (2018)
  5. Inhibitory-κB Kinase (IKK) α and Nuclear Factor-κB (NFκB)-Inducing Kinase (NIK) as Anti-Cancer Drug Targets. Paul A, Edwards J, Pepper C, Mackay S. Cells 7 E176 (2018)

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  2. Evidence for M1-Linked Polyubiquitin-Mediated Conformational Change in NEMO. Hauenstein AV, Xu G, Kabaleeswaran V, Wu H. J Mol Biol 429 3793-3800 (2017)
  3. Mechanism of vaccinia viral protein B14-mediated inhibition of IκB kinase β activation. Tang Q, Chakraborty S, Xu G. J Biol Chem 293 10344-10352 (2018)
  4. Nano NiO induced liver toxicity via activating the NF-κB signaling pathway in rats. Liu F, Chang X, Tian M, Zhu A, Zou L, Han A, Su L, Li S, Sun Y. Toxicol Res (Camb) 6 242-250 (2017)
  5. Berberine, A Phytoalkaloid, Inhibits Inflammatory Response Induced by LPS through NF-Kappaβ Pathway: Possible Involvement of the IKKα. Reddi KK, Li H, Li W, Tetali SD. Molecules 26 4733 (2021)
  6. Regulatory subunit NEMO promotes polyubiquitin-dependent induction of NF-κB through a targetable second interaction with upstream activator IKK2. Ko MS, Cohen SN, Polley S, Mahata SK, Biswas T, Huxford T, Ghosh G. J Biol Chem 298 101864 (2022)
  7. Molecular Mechanisms of the Toll-Like Receptor, STING, MAVS, Inflammasome, and Interferon Pathways. Manes NP, Nita-Lazar A. mSystems e0033621 (2021)
  8. Stress-induced inflammation evoked by immunogenic cell death is blunted by the IRE1α kinase inhibitor KIRA6 through HSP60 targeting. Rufo N, Korovesis D, Van Eygen S, Derua R, Garg AD, Finotello F, Vara-Perez M, Rožanc J, Dewaele M, de Witte PA, Alexopoulos LG, Janssens S, Sinkkonen L, Sauter T, Verhelst SHL, Agostinis P. Cell Death Differ 29 230-245 (2022)
  9. Integrating Network Pharmacology and Experimental Validation to Explore the Key Mechanism of Gubitong Recipe in the Treatment of Osteoarthritis. Chen GY, Liu XY, Luo J, Yu XB, Liu Y, Tao QW. Comput Math Methods Med 2022 7858925 (2022)
  10. Structurally plastic NEMO and oligomerization prone IKK2 subunits define the behavior of human IKK2:NEMO complexes in solution. Ko MS, Biswas T, Mulero MC, Bobkov AA, Ghosh G, Huxford T. Biochim Biophys Acta Proteins Proteom 1868 140526 (2020)
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  12. Novel biochemical, structural, and systems insights into inflammatory signaling revealed by contextual interaction proteomics. Ciuffa R, Uliana F, Uliana F, Mannion J, Mehnert M, Tenev T, Marulli C, Satanowski A, Keller LML, Rodilla Ramírez PN, Ori A, Gstaiger M, Meier P, Aebersold R. Proc Natl Acad Sci U S A 119 e2117175119 (2022)
  13. Voacanga globosa Spirobisindole Alkaloids Exert Antiviral Activity in HIV Latently Infected Cell Lines by Targeting the NF-kB Cascade: In Vitro and In Silico Investigations. de Jesus MSM, Macabeo APG, Ramos JDA, de Leon VNO, Asamitsu K, Okamoto T. Molecules 27 1078 (2022)
  14. Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα). Bainter W, Lougaris V, Wallace JG, Badran Y, Hoyos-Bachiloglu R, Peters Z, Wilkie H, Das M, Janssen E, Beano A, Farhat KB, Kam C, Bercich L, Incardona P, Villanacci V, Bondioni MP, Meini A, Baronio M, Abarzua P, Parolini S, Tabellini G, Maio S, Schmidt B, Goldsmith JD, Murphy G, Hollander G, Plebani A, Chou J, Geha RS. Sci Immunol 6 eabf6723 (2021)
  15. Modulation of Kinase Activities In Vitro by Hepatitis C Virus Protease NS3/NS4A Mediated-Cleavage of Key Immune Modulator Kinases. Abdullah MAF, McWhirter SM, Suo Z. Cells 12 406 (2023)
  16. Suppression of IKK, but not activation of p53 is responsible for cell death mediated by naturally occurring oxidized tetranortriterpenoid. Gupta P, Zaidi AH, Manna SK. J Cell Biochem 119 6828-6841 (2018)
  17. The host antiviral protein SAMHD1 suppresses NF-κB activation by interacting with the IKK complex during inflammatory responses and viral infection. Yang H, Espada CE, Phillips S, Martinez N, Kenney AD, Yount JS, Xiong Y, Wu L. J Biol Chem 299 104750 (2023)
  18. A Kinase Assay for Measuring the Activity of the NIK-IKK1 Complex Induced via the Noncanonical NF-κB Pathway. Mukherjee T, Ratra Y, Banoth B, Deka A, Polley S, Basak S. Methods Mol Biol 2366 165-181 (2021)


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