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Mechanism of E-cadherin dimerization probed by NMR relaxation dispersion
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 110(41)
- Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Models, Molecular
Multidisciplinary
Magnetic Resonance Spectroscopy
Chemistry
Cadherin
Protein Conformation
Dimer
Nuclear magnetic resonance spectroscopy
Biological Sciences
Cadherins
Receptor–ligand kinetics
Fluorescence
Protein–protein interaction
Adherens junction
Crystallography
chemistry.chemical_compound
Mice
Protein structure
Cell Adhesion
Intermediate state
Animals
Dimerization
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 110
- Issue :
- 41
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....2640ba1094ec579468815458bec815bf