Functional analysis of the structural basis of homophilic cadherin adhesion.
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.
Zhu
B
B
Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, Illinois 61801, USA.
Chappuis-Flament
S
S
Wong
E
E
Jensen
I E
IE
Gumbiner
B M
BM
Leckband
D
D
D001665:Binding Sites; D015820:Cadherins / Q000737:chemistry* / Q000145:classification*; D002448:Cell Adhesion / Q000502:physiology; D019281:Dimerization; D004548:Elasticity; D004735:Energy Transfer; D046911:Macromolecular Substances; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013314:Stress, Mechanical; D013329:Structure-Activity Relationship; D013499:Surface Properties
D015820:Cadherins; D046911:Macromolecular Substances