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J. Biol. Chem., Vol. 279, Issue 52, 54750-54758, December 24, 2004

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Crystal Structure of the Kelch Domain of Human Keap1^*

Xuchu Li, Donna Zhang, Mark Hannink, and Lesa J. Beamer¶

From the Department of Biochemistry and the Life Sciences Center, University of Missouri-Columbia, Columbia, Missouri 65211

Keap1 is a substrate adaptor protein for an ubiquitin ligase complex that targets the Nrf2 transcription factor for degradation. Keap1 binds Nrf2 through its C-terminal Kelch domain, which contains six copies of the evolutionarily conserved kelch repeat sequence motif. The structure of the Kelch domain from human Keap1 has been determined by x-ray crystallography to a resolution of 1.85 Å. The Kelch domain forms a 6-bladed -propeller structure, with residues at the C terminus forming the first strand in the first blade. Key structural roles have been identified for the highly conserved glycine, tyrosine, and tryptophan residues that define the kelch repeat sequence motif. In addition, we show that substitution of a single amino acid located within a loop that extends out from the bottom of the -propeller structure abolishes binding of Nrf2. The structure of the Kelch domain of Keap1 represents a high quality model for the superfamily of eukaryotic kelch repeat proteins and provides insight into how disease-causing mutations perturb the structural integrity of the Kelch domain.

Received for publication, September 1, 2004 , and in revised form, October 4, 2004.

The atomic coordinates and structure factors (code 1U6D) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the University of Missouri Molecular Biology Program, the University of Missouri Food for the 21st Century program, Research Grants GM59213 and P50 CA103130 from the National Institutes of Health, and by a grant from the University of Missouri Research Board. 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. Tel.: 573-882-6072; Fax: 573-884-4812; E-mail: Beamerl{at}missouri.edu.

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