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Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16462-7. doi: 10.1073/pnas.1314303110. Epub 2013 Sep 25.

Mechanism of E-cadherin dimerization probed by NMR relaxation dispersion.

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Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, and Edward S. Harkness Eye Institute, Columbia University, New York, NY 10032.

Erratum in

  • Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19651.


Epithelial cadherin (E-cadherin), a member of the classical cadherin family, mediates calcium-dependent homophilic cell-cell adhesion. Crystal structures of classical cadherins reveal an adhesive dimer interface featuring reciprocal exchange of N-terminal β-strands between two protomers. Previous work has identified a putative intermediate (called the "X-dimer") in the dimerization pathway of wild-type E-cadherin EC1-EC2 domains, based on crystal structures of mutants not capable of strand swapping and on deceleration of binding kinetics by mutations at the X-dimer interface. In the present work, NMR relaxation dispersion spectroscopy is used to directly observe and characterize intermediate states without the need to disrupt the strand-swapped binding interface by mutagenesis. The results indicate that E-cadherin forms strand-swapped dimers predominantly by a mechanism in which formation of a weak and short-lived X-dimer-like state precedes the conformational changes required for formation of the mature strand-swapped dimeric structure. Disruption of this intermediate state through mutation reduces both association and dissociation rates by factors of ~10(4), while minimally perturbing affinity. The X-dimer interface lowers the energy barrier associated with strand swapping and enables E-cadherins to form strand-swapped dimers at a rate consistent with residence times in adherens junctions.


binding mechanism; domain swapping; protein-protein interaction

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