Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site |
| |
Authors: | Rushe Mia Silvian Laura Bixler Sarah Chen Ling Ling Cheung Anne Bowes Scott Cuervo Hernan Berkowitz Steven Zheng Timothy Guckian Kevin Pellegrini Maria Lugovskoy Alexey |
| |
Affiliation: | Biogen Idec Inc., Cambridge, MA 02142, USA. |
| |
Abstract: | The phosphorylation of IkappaB by the IKK complex targets it for degradation and releases NF-kappaB for translocation into the nucleus to initiate the inflammatory response, cell proliferation, or cell differentiation. The IKK complex is composed of the catalytic IKKalpha/beta kinases and a regulatory protein, NF-kappaB essential modulator (NEMO; IKKgamma). 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|