NDLI: A Structural Basis for IκB Kinase 2 Activation Via Oligomerization-Dependent Trans Auto-Phosphorylation

Content Provider	PubMed Central
Author	Polley, Smarajit Huang, De-bin Hauenstein, Arthur V. Fusco, Amanda J. Zhong, Xiangyang Vu, Don Schröfelbauer, Bärbel Kim, Youngchang Hoffmann, Alexander Verma, Inder M. Ghosh, Gourisankar Huxford, Tom
Editor	Petsko, Gregory A.
Copyright Year	2013
Abstract	Activation of the IκB kinase (IKK) is central to NF-κB signaling. However, the precise activation mechanism by which catalytic IKK subunits gain the ability to induce NF-κB transcriptional activity is not well understood. Here we report a 4 Å x-ray crystal structure of human IKK2 (hIKK2) in its catalytically active conformation. The hIKK2 domain architecture closely resembles that of Xenopus IKK2 (xIKK2). However, whereas inactivated xIKK2 displays a closed dimeric structure, hIKK2 dimers adopt open conformations that permit higher order oligomerization within the crystal. Reversible oligomerization of hIKK2 dimers is observed in solution. Mutagenesis confirms that two of the surfaces that mediate oligomerization within the crystal are also critical for the process of hIKK2 activation in cells. We propose that IKK2 dimers transiently associate with one another through these interaction surfaces to promote trans auto-phosphorylation as part of their mechanism of activation. This structure-based model supports recently published structural data that implicate strand exchange as part of a mechanism for IKK2 activation via trans auto-phosphorylation. Moreover, oligomerization through the interfaces identified in this study and subsequent trans auto-phosphorylation account for the rapid amplification of IKK2 phosphorylation observed even in the absence of any upstream kinase.
Related Links	http://dx.doi.org/10.1371/journal.pbio.1001581
Starting Page	1001581
File Format	PDF
ISSN	15457885
e-ISSN	15457885
Journal	PLoS Biology
Issue Number	6
Volume Number	11
Language	English
Publisher	Public Library of Science
Publisher Date	2013-06-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Immunology and Microbiology(all) Neuroscience(all) Agricultural and Biological Sciences(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Microbiology Biochemistry, Genetics and Molecular Biology Agricultural and Biological Sciences

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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