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Functional Analysis of the Structural Basis of Homophilic Cadherin Adhesion

B. Zhu ^*, S. Chappuis-Flament , E. Wong , I. E. Jensen , B. M. Gumbiner ^¶ and D. Leckband ^* 

^* Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, Illinois 61801 USA; TRANSAT, Faculté de Médecine, 69373 Lyon Cedex 08, France; Department of Cell Biology, Rockefeller University, New York, New York 10021 USA; Department of Biochemistry, University of Illinois, Urbana, Illinois 61801 USA; and ^¶ Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908 USA

Correspondence: Address reprint requests to D. Leckband, Dept. of Chemical and Biomolecular Engineering, University of Illinois, 600 S. Mathews Ave., Urbana, IL 61801. Tel.: 217-244-0793; Fax: 217-333-5052; E-mail: leckband{at}uiuc.edu.

The structures of many cell surface adhesion proteins comprise multiple tandem repeats of structurally similar domains. In many cases, the functional significance of this architecture is unknown, and there are several cases in which evidence for individual domain involvement in adhesion has been contradictory. In particular, the extracellular region of the adhesion glycoprotein cadherin consists of five tandemly arranged domains. One proposed mechanism postulated that adhesion involves only trans interactions between the outermost domains. However, subsequent investigations have generated several competing models. Here we describe direct measurements of the distance-dependent interaction potentials between cadherin mutants lacking different domains. By quantifying both the absolute distances at which opposed cadherin fragments bind and the quantized changes in the interaction potentials that result from deletions of individual domains, we demonstrate that two domains participate in homophilic cadherin binding. This finding contrasts with the current view that cadherins bind via a single, unique site on the protein surface. The potentials that result from interactions involving multiple domains generate a novel, modular binding mechanism in which opposed cadherin ectodomains can adhere in any of three antiparallel alignments.

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