1. Structure of a NEMO/IKK-Associating Domain Reveals Architecture of the Interaction Site
- Author
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Rushe, Mia, Silvian, Laura, Bixler, Sarah, Chen, Ling Ling, Cheung, Anne, Bowes, Scott, Cuervo, Hernan, Berkowitz, Steven, Zheng, Timothy, Guckian, Kevin, Pellegrini, Maria, and Lugovskoy, Alexey
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CELL nuclei , *ORGANELLES , *ANUCLEATE cells , *CHROMOSOMES - Abstract
Summary: The phosphorylation of IκB by the IKK complex targets it for degradation and releases NF-κB for translocation into the nucleus to initiate the inflammatory response, cell proliferation, or cell differentiation. The IKK complex is composed of the catalytic IKKα/β kinases and a regulatory protein, NF-κB essential modulator (NEMO; IKKγ). NEMO associates with the unphosphorylated IKK kinase C termini and activates the IKK complex''s catalytic activity. However, detailed structural information about the NEMO/IKK interaction is lacking. In this study, we have identified the minimal requirements for NEMO and IKK kinase association using a variety of biophysical techniques and have solved two crystal structures of the minimal NEMO/IKK kinase associating domains. We demonstrate that the NEMO core domain is a dimer that binds two IKK fragments and identify energetic hot spots that can be exploited to inhibit IKK complex formation with a therapeutic agent. [Copyright &y& Elsevier]
- Published
- 2008
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