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J. Biol. Chem., Vol. 279, Issue 44, 45528-45539, October 29, 2004

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A Novel Ubiquitin-like Domain in IB Kinase Is Required for Functional Activity of the Kinase^*

Michael J. May, Signe E. Larsen, Jae Hyuck Shim, Lisa A. Madge, and Sankar Ghosh¶

From the Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104 and Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University Medical School, New Haven, Connecticut 06520

Activation of NF-B requires two highly related kinases named IKK and IKK that share identity in the nature and positioning of their structural domains. Despite their similarity, the kinases are functionally divergent, and we therefore sought to identify any structural features specific for IKK or IKK. We performed bioinformatics analysis, and we identified a region resembling a ubiquitin-like domain (UBL) that exists only in IKK and that we named the UBL-like domain (ULD). Deletion of the ULD rendered IKK catalytically inactive and unable to induce NF-B activity, and overexpression of only the ULD dose-dependently inhibited tumor necrosis factor--induced NF-B activity. The ULD could not be functionally replaced within IKK by ubiquitin or the corresponding region of IKK, whereas deletion of the equivalent section of IKK did not affect its catalytic activity against IB or its activation by NF-B-inducing kinase. We identified five residues conserved among the larger family of UBL-containing proteins and IKK, and alanine scanning revealed that the leucine at position 353 (Leu³⁵³) is absolutely critical for IKK-induced NF-B activation. Most intriguingly, the L353A mutant was catalytically active but, unlike wild-type IKK, formed a stable complex with the NF-B p65 subunit. Our findings therefore establish the ULD as a critical functional domain specific for IKK that might play a role in dissociating IKK from p65.

Received for publication, July 28, 2004

^* This work was supported by National Institutes of Health Grant R37-AI33443, by a scientist development grant from the American Heart Association (to M. J. M.), and in part by the Abramson Cancer Center of the University of Pennsylvania. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Section of Immunobiology and Dept. of Molecular Biophysics and Biochemistry, Yale University Medical School, 310 Cedar St., New Haven, CT 06520. Tel.: 203-737-4419; Fax: 203-737-1764; E-mail: sankar.ghosh{at}yale.edu.

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