Specificity of cell-cell adhesion by classical cadherins: Critical role for low-affinity dimerization through beta-strand swapping.
Cadherins constitute a family of cell-surface proteins that mediate intercellular adhesion through the association of protomers presented from juxtaposed cells. Differential cadherin expression leads to highly specific intercellular interactions in vivo. This cell-cell specificity is difficult to understand at the molecular level because individual cadherins within a given subfamily are highly similar to each other both in sequence and structure, and they dimerize with remarkably low binding affinities. Here, we provide a molecular model that accounts for these apparently contradictory observations. The model is based in part on the fact that cadherins bind to one another by "swapping" the N-terminal beta-strands of their adhesive domains. An inherent feature of strand swapping (or, more generally, the domain swapping phenomenon) is that "closed" monomeric conformations act as competitive inhibitors of dimer formation, thus lowering affinities even when the dimer interface has the characteristics of high-affinity complexes. The model describes quantitatively how small affinity differences between low-affinity cadherin dimers are amplified by multiple cadherin interactions to establish large specificity effects at the cellular level. It is shown that cellular specificity would not be observed if cadherins bound with high affinities, thus emphasizing the crucial role of strand swapping in cell-cell adhesion. Numerical estimates demonstrate that the strength of cellular adhesion is extremely sensitive to the concentration of cadherins expressed at the cell surface. We suggest that the domain swapping mechanism is used by a variety of cell-adhesion proteins and that related mechanisms to control affinity and specificity are exploited in other systems.
Chen
Chien Peter
CP
Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168 Street, New York, NY 10032, USA.
Posy
Shoshana
S
Ben-Shaul
Avinoam
A
Shapiro
Lawrence
L
Honig
Barry H
BH
D000595:Amino Acid Sequence; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D019281:Dimerization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000502:physiology*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D015820:Cadherins