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J. Biol. Chem., Vol. 283, Issue 26, 18056-18065, June 27, 2008

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Crystal Structure of HAb18G/CD147

IMPLICATIONS FOR IMMUNOGLOBULIN SUPERFAMILY HOMOPHILIC ADHESION^*

Xiao-Ling Yu¹, Tiancen Hu¹, Jia-Mu Du^¶1, Jian-Ping Ding^¶1, Xiang-Min Yang, Jian Zhang, Bin Yang, Xu Shen, Zheng Zhang, Wei-De Zhong^||, Ning Wen^**, Hualiang Jiang, Ping Zhu², and Zhi-Nan Chen³

From the Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, and the Department of Clinical Immunology, Xijing Hospital, the Fourth Military Medical University, 17 West Changle Road, Xi'an 710032, the Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai 201203, the ^¶State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, ^||Guangzhou First Municipal People's Hospital, Guangzhou Medical College, Dongfeng Xi Road, Guangzhou 510182, and ^**Chinese People's Liberation Army General Hospital, 28 Fuxing Road, Beijing 100853, China

CD147, a member of the immunoglobulin superfamily (IgSF), plays fundamental roles in intercellular interactions in numerous pathological and physiological processes. Importantly, our previous studies have demonstrated that HAb18G/CD147 is a novel hepatocellular carcinoma (HCC)-associated antigen, and HAb18G/CD147 stimulates adjacent fibroblasts and HCC cells to produce elevated levels of several matrix metalloproteinases, facilitating invasion and metastasis of HCC cells. In addition, HAb18G/CD147 has also been shown to be a novel universal cancer biomarker for diagnosis and prognostic assessment of a wide range of cancers. However, the structural basis underlying the multifunctional character of CD147 remains unresolved. We report here the crystal structure of the extracellular portion of HAb18G/CD147 at 2.8Å resolution. The structure comprises an N-terminal IgC2 domain and a C-terminal IgI domain, which are connected by a 5-residue flexible linker. This unique C2-I domain organization is distinct from those of other IgSF members. Four homophilic dimers exist in the crystal and adopt C2-C2 and C2-I dimerization rather than V-V dimerization commonly found in other IgSF members. This type of homophilic association thus presents a novel model for homophilic interaction between C2 domains of IgSF members. Moreover, the crystal structure of HAb18G/CD147 provides a good structural explanation for the established multifunction of CD147 mediated by homo/hetero-oligomerizations and should represent a general architecture of other CD147 family members.

Received for publication, April 8, 2008 , and in revised form, April 22, 2008.

The atomic coordinates and structure factors (code 3B5H) 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 National Basic Research Program of China (Grant 2006CB708504), the National Natural Science Foundation of China (Grants 30530720 and 20721003), the Hi-tech Research and Development Program of China (Grant 2006AA02A253), and the Ministry of Science and Technology of China (Grants 2004CB720102 and 2006AA02Z112). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2, Table S1, and additional text and references.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Tel.: 86-29-8477-5355; Fax: 86-29-8329-3906; E-mail: zhuping{at}fmmu.edu.cn. ³ To whom correspondence should be addressed: Tel.: 86-29-8477-4545; Fax: 86-29-8329-3906; E-mail: zhinanchen{at}fmmu.edu.cn.

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