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J. Biol. Chem., Vol. 280, Issue 6, 5054-5060, February 11, 2005

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Axin Contains Three Separable Domains That Confer Intramolecular, Homodimeric, and Heterodimeric Interactions Involved in Distinct Functions^*

Wen Luo, Haiying Zou, Lihua Jin, Shuyong Lin, Qinxi Li, Zhiyun Ye, Hongliang Rui, and Sheng-Cai Lin, A recipient of National Outstanding Young Investigator Award 30125012¶

From the Department of Biomedical Sciences and the Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China and Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

Axin is a major scaffold protein, interacting with diverse molecules involved in a number of signaling pathways. Axin can undergo dimer/oligomerization via its DIX domain. Here we show that whereas deletion of the DIX domain at the C terminus rendered Axin incapable of forming dimer, a larger deletion of the C-terminal region restored the ability of Axin to form dimers. Detailed analyses revealed that Axin actually contains two separate domains (D and I) in addition to the DIX domain for homodimerization. The D, I, and DIX domains alone can form homodimers. Interestingly, D and I domains strongly interact with each other, suggesting that Axin can form an intramolecular structure through D and I interaction in the absence of DIX. We also found that DIX-DIX homodimeric interaction is weak but that point mutations in the DIX domain abolished Axin homodimerization. We propose a model to suggest that Axin forms homodimeric interactions through three domains, D, I, and DIX. More importantly, lack of DIX-DIX interaction caused by point mutations in the DIX domain or deletion causes Axin to form an intramolecular loop through the D and I domains, disallowing homodimer formation. Ccd1 interacts with Axin D domain yet fails to interact with AxinDIX, confirming that D is masked after D-I looping. The Axin mutants that are defective in homodimer formation fail to activate JNK but have no effect on -catenin signaling. Our findings have thus provided a structural basis of conformational changes in Axin, which may underlie the diversity of Axin functions.

Received for publication, November 1, 2004 , and in revised form, December 1, 2004.

^* This work was supported in part by Grant 2002AA629060 from the "863" Program of the Ministry of Science and Technology of China, Grant 2002F002 from the Fujian Council of Science and Technology, Grants 90208015 and 30370306 from the Natural Sciences Foundation of China, and Grants HKUST 6122/02M and 6141/03M from the Research Grants Council of Hong Kong. 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: Dept. of Biomedical Sciences and the Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Fujian 361005, China. Tel.: 852-2358-7294; Fax: 852-2358-1552; E-mail: linsc{at}mxu.edu.cn.

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