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J. Biol. Chem., Vol. 282, Issue 17, 12734-12740, April 27, 2007

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Disruption of the GDNF Binding Site in NCAM Dissociates Ligand Binding and Homophilic Cell Adhesion^*

Dan Sjöstrand, Jonas Carlsson, Gustavo Paratcha¹, Bengt Persson^¶, and Carlos F. Ibáñez²

From the Division of Molecular Neurobiology, Department of Neuroscience, and ^¶Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden and IFM Bioinformatics, Linköping University, S-581 83 Linköping, Sweden

Most plasma membrane proteins are capable of sensing multiple cell-cell and cell-ligand interactions, but the extent to which this functional versatility is founded on their modular design is less clear. We have identified the third immunoglobulin domain of the Neural Cell Adhesion Molecule (NCAM) as the necessary and sufficient determinant for its interaction with Glial Cell Line-derived Neurotrophic Factor (GDNF). Four charged contacts were identified by molecular modeling as the main contributors to binding energy. Their mutation abolished GDNF binding to NCAM but left intact the ability of NCAM to mediate cell adhesion, indicating that the two functions are genetically separable. The GDNF-NCAM interface allows complex formation with the GDNF family receptor 1, shedding light on the molecular architecture of a multicomponent GDNF receptor.

Received for publication, February 22, 2007

^* This work was supported by grants from the Swedish Foundation for Strategic Research, the Swedish Research Council (33X-10908-10A and 2004-6434), the Swedish Cancer Society (3474-B97-05XBC), the Vth Framework Program of the European Commission (QLG3-CT-2002-01000), the Karolinska Institute (to C. F. I.), and Linköping University (to B. P.). 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 the coordinates of model in Fig. 2A.

¹ Supported by the Swedish Research Council. Currently affilited with the Laboratory of Molecular and Cellular Neuroscience, Dept. of Neuroscience, Karolinska Institute.

² To whom correspondence should be addressed. Tel.: 46-8-5248-7660; Fax: 46-8-33-95-48; E-mail: carlos.ibanez{at}ki.se.

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