{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:16:42Z","timestamp":1785428202896,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,1]]},"group-title":"Immunology","reference-count":26,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01AI163327"],"award-info":[{"award-number":["R01AI163327"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01GM085490"],"award-info":[{"award-number":["R01GM085490"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The inhibitor of \u03baB kinase (IKK) complex integrates diverse cellular inflammatory responses, and induces transcription factor NF-\u03baB. The molecular mechanism by which IKK becomes catalytically active in response to signaling remains unclear despite structural knowledge of the individual IKK1\/\u03b1, IKK2\/\u03b2, and NEMO\/IKK\u03b3 protein components within its hetero-oligomeric assembly. Cryo-EM of the IKK2\/\u03b2 homodimer bound to an associating NEMO\/IKK\u03b3 protein fragment, reveals multiple conformers. Mutual exclusivity of dimeric conformers, canonical versus alternate, is reflected in and dependent upon order-to-disorder transition of the canonical 6-helical bundle dimerization interface. Correlation of this unusual structural plasticity of IKK2\/\u03b2 with its biochemical and cellular activities suggests mechanistic possibilities for how association with its partner scaffold protein NEMO\/IKK\u03b3 and polyubiquitin chains might dictate catalytic activation of IKK through distinct IKK2\/\u03b2 conformers.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>The inhibitor of \u03baB kinase (IKK) complex is central to inflammatory signaling via the NF-\u03baB family transcription factors. Its activation mechanism has remained unclear. Cryo-EM analysis reveals that the constituent kinase IKK2\/\u03b2 adopts structurally distinct, mutually exclusive dimeric conformations controlled by an ordered-to-disordered transition at its canonical dimerization interface. Stabilization of select IKK2\/\u03b2 conformers by the scaffold protein NEMO in association with poly-ubiquitin chains is regulated through modular architecture and structural plasticity of distinctive kinase-associated domains, present only in kinases of this family. This unique regulatory mechanism governing catalytic activation of IKK2\/\u03b2 provides a conceptual framework for targeting dysregulated NF-\u03baB signaling in human diseases.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.29.735262","type":"posted-content","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T23:20:17Z","timestamp":1782948017000},"source":"Crossref","is-referenced-by-count":0,"title":["Cryo-EM reveals alternative modes of dimerization driving activation of IKK"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9460-1813","authenticated-orcid":false,"given":"Tapan","family":"Biswas","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8462-4520","authenticated-orcid":false,"given":"Shandy","family":"Shahabi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Yang","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0053-3697","authenticated-orcid":false,"given":"Myung Soo","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093"},{"name":"Structural Biochemistry Laboratory, Department of Chemistry & Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1939-7373","authenticated-orcid":false,"given":"Tom","family":"Huxford","sequence":"additional","affiliation":[{"name":"Structural Biochemistry Laboratory, Department of Chemistry & Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6311-7351","authenticated-orcid":false,"given":"Gourisankar","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070401550690000_2026.06.29.735262v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/41493"},{"key":"2026070401550690000_2026.06.29.735262v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80406-7"},{"key":"2026070401550690000_2026.06.29.735262v1.3","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5339.866"},{"key":"2026070401550690000_2026.06.29.735262v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5339.860"},{"key":"2026070401550690000_2026.06.29.735262v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/26261"},{"key":"2026070401550690000_2026.06.29.735262v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81466-X"},{"key":"2026070401550690000_2026.06.29.735262v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00741-9"},{"key":"2026070401550690000_2026.06.29.735262v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.08.024"},{"key":"2026070401550690000_2026.06.29.735262v1.9","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.9.8.7768349"},{"key":"2026070401550690000_2026.06.29.735262v1.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.482596"},{"key":"2026070401550690000_2026.06.29.735262v1.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001581"},{"key":"2026070401550690000_2026.06.29.735262v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.10.067"},{"key":"2026070401550690000_2026.06.29.735262v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/nature09853"},{"key":"2026070401550690000_2026.06.29.735262v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.01.033"},{"key":"2026070401550690000_2026.06.29.735262v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/ni921"},{"key":"2026070401550690000_2026.06.29.735262v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2008.02.012"},{"key":"2026070401550690000_2026.06.29.735262v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.52"},{"key":"2026070401550690000_2026.06.29.735262v1.18","doi-asserted-by":"publisher","DOI":"10.1126\/stke.3572006re13"},{"key":"2026070401550690000_2026.06.29.735262v1.19","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5412.316"},{"key":"2026070401550690000_2026.06.29.735262v1.20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2012.01108.x"},{"key":"2026070401550690000_2026.06.29.735262v1.21","doi-asserted-by":"crossref","first-page":"7692","DOI":"10.1038\/s41467-024-52076-0","article-title":"Molecular mechanism of IKK catalytic dimer docking to NF-kappaB substrates","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026070401550690000_2026.06.29.735262v1.22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304374200"},{"key":"2026070401550690000_2026.06.29.735262v1.23","doi-asserted-by":"crossref","first-page":"101864","DOI":"10.1016\/j.jbc.2022.101864","article-title":"Regulatory subunit NEMO promotes polyubiquitin-dependent induction of NF-kappaB through a targetable second interaction with upstream activator IKK2","volume":"298","year":"2022","journal-title":"J Biol Chem"},{"key":"2026070401550690000_2026.06.29.735262v1.24","doi-asserted-by":"publisher","DOI":"10.1021\/bi401551r"},{"key":"2026070401550690000_2026.06.29.735262v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1228-x"},{"key":"2026070401550690000_2026.06.29.735262v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.01.034"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.29.735262","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T08:55:12Z","timestamp":1783155312000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.29.735262"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":26,"URL":"https:\/\/doi.org\/10.64898\/2026.06.29.735262","relation":{},"subject":[],"published":{"date-parts":[[2026,7,1]]},"subtype":"preprint"}}