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J. Biol. Chem., Vol. 281, Issue 25, 17400-17409, June 23, 2006

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Crystal Structure of the Human FOXK1a-DNA Complex and Its Implications on the Diverse Binding Specificity of Winged Helix/Forkhead Proteins^*

Kuang-Lei Tsai, Cheng-Yang Huang, Chia-Hao Chang^¶, Yuh-Ju Sun, Woei-Jer Chuang^¶1, and Chwan-Deng Hsiao²

From the Institute of Molecular Biology, Academia Sinica, Taipei 115, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, and ^¶Department of Biochemistry, National Cheng Kung University, College of Medicine, Tainan 701, Taiwan

Interleukin enhancer binding factor (ILF) is a human transcription factor and a new member of the winged helix/forkhead family. ILF can bind to purine-rich regulatory motifs such as the human T-cell leukemia virus-long terminal region and the interleukin-2 promoter. Here we report the 2.4 Å crystal structure of two DNA binding domains of ILF (FOXK1a) binding to a 16-bp DNA duplex containing a promoter sequence. Electrophoretic mobility shift assay studies demonstrate that two ILF-DNA binding domain molecules cooperatively bind to DNA. In addition to the recognition helix recognizing the core sequences through the major groove, the structure shows that wing 1 interacts with the minor groove of DNA, and the H2-H3 loop region makes ionic bonds to the phosphate group, which permits the recognition of DNA. The structure also reveals that the presence of the C-terminal -helix in place of a typical wing 2 in a member of this family alters the orientation of the C-terminal basic residues (RKRRPR) when binding to DNA outside the core sequence. These results provide a new insight into how the DNA binding specificities of winged helix/forkhead proteins may be regulated by their less conserved regions.

Received for publication, January 17, 2006 , and in revised form, April 12, 2006.

The atomic coordinates and structure factors (code 2C6Y) 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 Academia Sinica and the National Science Council Grant NSC94-2311-B-001-015 (to C.-D. H.). 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.

¹ To whom correspondence should be addressed. Tel.: 886-6-235-3535 (ext. 5515); Fax: 886-6-274-1694; E-mail: wjcnmr{at}mail.ncku.edu.tw. ² To whom correspondence should be addressed. Tel.: 886-2-2788-2743; Fax: 886-2-2782-6085; E-mail: hsiao{at}gate.sinica.edu.tw.

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