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J. Biol. Chem., Vol. 283, Issue 34, 23485-23495, August 22, 2008

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Insights into the Low Adhesive Capacity of Human T-cadherin from the NMR Structure of Its N-terminal Extracellular Domain^*

Sonja A. Dames¹², Eunjung Bang¹³, Daniel Haüssinger, Thomas Ahrens, Jürgen Engel, and Stephan Grzesiek⁴

From the Departments of Structural Biology and Biophysical Chemistry, Biozentrum, University of Basel, Klingelbergstr. 70, 4056 Basel, Switzerland

T-cadherin is unique among the family of type I cadherins, because it lacks transmembrane and cytosolic domains, and attaches to the membrane via a glycophosphoinositol anchor. The N-terminal cadherin repeat of T-cadherin (Tcad1) is 30% identical to E-, N-, and other classical cadherins. However, it lacks many amino acids crucial for their adhesive function of classical cadherins. Among others, Trp-2, which is the key residue forming the canonical strand-exchange dimer, is replaced by an isoleucine. Here, we report the NMR structure of the first cadherin repeat of T-cadherin (Tcad1). Tcad1, as other cadherin domains, adopts a β-barrel structure with a Greek key folding topology. However, Tcad1 is monomeric in the absence and presence of calcium. Accordingly, lle-2 binds into a hydrophobic pocket on the same protomer and participates in an N-terminal β-sheet. Specific amino acid replacements compared to classical cadherins reduce the size of the binding pocket for residue 2 and alter the backbone conformation and flexibility around residues 5 and 15 as well as many electrostatic interactions. These modifications apparently stabilize the monomeric form and make it less susceptible to a conformational switch upon calcium binding. The absence of a tendency for homoassociation observed by NMR is consistent with electron microscopy and solid-phase binding data of the full T-cadherin ectodomain (Tcad1-5). The apparent low adhesiveness of T-cadherin suggests that it is likely to be involved in reversible and dynamic cellular adhesion-deadhesion processes, which are consistent with its role in cell growth and migration.

Received for publication, October 9, 2007 , and in revised form, May 26, 2008.

The atomic coordinates and structure factors (code 2V37) 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 in part by the Canton of Basel and Swiss National Science Foundation Grants 31-109712 (to S. G.) and 31-49281.96 (to J. E.). 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 data, references, and Figs. S1-S5.

¹ Both authors contributed equally to this work.

³ Supported by the Korea Research Foundation (Grant KRF-2003-214-C00236). Present address: Korea Basic Science Institute, Seoul Center, Seoul 136-701, Korea.

² To whom correspondence may be addressed: Dept. of Structural Biology, Biozentrum, University of Basel, Klingelbergstr. 70, 4056 Basel, Switzerland. Tel.: 41-61-2672106; Fax: 41-61-2672109; E-mail: sonja.dames{at}unibas.ch.

⁴ To whom correspondence may be addressed: Dept. of Structural Biology, Biozentrum, University of Basel, Klingelbergstr. 70, 4056 Basel, Switzerland. Tel.: 41-61-2672100; Fax: 41-61-2672109; E-mail: stephan.grzesiek{at}unibas.ch.

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