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Structure-function analysis of cell adhesion by neural (N-) cadherin
K Tamura1, W S Shan, W A Hendrickson
1Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract:
To investigate the possible biological function of the lateral "strand dimer" observed in crystal structures of a D1 domain extracellular fragment from N-cadherin, we have undertaken site-directed mutagenesis studies of this molecule. Mutation of most residues important in the strand dimer interface abolish the ability of N-cadherin to mediate cell adhesion. Mutation of an analogous central residue (Trp-2) in E-cadherin also abrogates the adhesive capacity of that molecule. We also determined the crystal structure of a Ca2+-complexed two-domain fragment from N-cadherin. This structure, like its E-cadherin counterpart, does not adopt the strand dimer conformation. This suggests the possibility that classical cadherins might stably exist in both dimeric and monomeric forms. Data from several laboratories imply that lateral dimerization or clustering of cadherins may increase their adhesivity. We suggest the possibility that the strand dimer may play a role in this activation.
Insights
Site-directed mutagenesis reveals that the N-cadherin strand dimer interface is crucial for cell adhesion. This suggests cadherins may exist in monomeric and dimeric forms, with the strand dimer potentially activating adhesion.
Area of Science:
- Cell adhesion
- Structural biology
- Molecular biology
Background:
- Cadherins mediate cell-cell adhesion, crucial for tissue development and integrity.
- The lateral "strand dimer" in N-cadherin's D1 domain has an unknown biological function.
- Previous studies suggest cadherin dimerization/clustering enhances adhesion.
Purpose of the Study:
- To investigate the biological role of the N-cadherin strand dimer.
- To explore the structural basis of cadherin-mediated cell adhesion.
Main Methods:
- Site-directed mutagenesis of N-cadherin and E-cadherin.
- Cell adhesion assays.
- Crystal structure determination of a Ca2+-complexed N-cadherin fragment.
Main Results:
- Mutations at the strand dimer interface abolish N-cadherin's cell adhesion ability.
- A similar mutation in E-cadherin also abrogates its adhesive capacity.
- The crystal structure of a Ca2+-bound N-cadherin fragment does not show the strand dimer conformation, suggesting stable monomeric and dimeric forms.
Conclusions:
- The strand dimer interface is essential for classical cadherin-mediated cell adhesion.
- Classical cadherins may exist in both monomeric and dimeric states.
- The strand dimer might play a role in activating cadherin adhesion, potentially through lateral dimerization or clustering.