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Figure 8


Fig. 8. Possible models for AJ reinforcement in differentiated myofibroblasts. In our experiments, the reinforcement of OB-cadherin bonds using either recombinant cadherin dimers or intact differentiated myofibroblasts, follows a sequence of maturation steps, always revealing three distinct force states. Different models can explain these states. (A) In the `zipper' model, the EC1 domains of cadherin monomers or dimers (here presented for dimers) of two cells trans-interact. Multiple force states are created by increasing the number of laterally (cis-) associating cadherins in the plasma membrane. (B) The interdigitation model predicts that three force states are achieved at the single-molecule level. Here, consecutive and homotypic interdigitation of the EC domains 1-3 increases binding strength: being weak when EC1-EC1 interact, of medium strength during interaction of EC2-EC2 and strongest when the inner EC3-EC3 domains interact. (C) Models A and B are in conflict with structural data obtained from monomeric C-cadherin favoring a trans-`strand-dimer' model. Bent cadherin monomers trans-interact with their EC1 domains through binding of a flexible Trp residue to a hydrophobic pocket (not displayed). In addition to this trans-interaction, hydrophobic domains in EC1 and EC2 can cis-interact. To explain three distinct force states with this model, one has to assume multimer formation. (D) The synthesis of models B and C can explain both structural and functional data. Bent cadherins (here presented for dimers) trans-interact laterally through a sequence of homotypic EC domain interactions. With increasing alignment, this model predicts increasing single-bond strength and shortening of the junction. Owing to the rigid conformation of the cadherin molecules, more than three force states may be energetically unfavorable, but still possible. In all models, EC domains that contribute to trans binding are highlighted in red.





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