AI Article Synopsis
- Cell adhesion in classical cadherins occurs through the dimerization of their EC1 domains, involving a 'swapping' mechanism of N-terminal β-strands.
- Researchers employed molecular simulations, binding affinity measurements, and X-ray crystallography to understand the structural and energetic factors influencing cadherin dimerization.
- The study reveals that dimerization is driven by conformational strain within cadherin monomers and highlights a conserved proline-proline motif that regulates the interface's strength and affinity differences among cadherins, leading to the design of mutations to create a new dimeric cadherin construct.
Article Abstract
Cell adhesion by classical cadherins is mediated by dimerization of their EC1 domains through the 'swapping' of N-terminal β-strands. We use molecular simulations, measurements of binding affinities and X-ray crystallography to provide a detailed picture of the structural and energetic factors that control the adhesive dimerization of cadherins. We show that strand swapping in EC1 is driven by conformational strain in cadherin monomers that arises from the anchoring of their short N-terminal strand at one end by the conserved Trp2 and at the other by ligation to Ca(2+) ions. We also demonstrate that a conserved proline-proline motif functions to avoid the formation of an overly tight interface where affinity differences between different cadherins, crucial at the cellular level, are lost. We use these findings to design site-directed mutations that transform a monomeric EC2-EC3 domain cadherin construct into a strand-swapped dimer.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113550 | PMC |
| http://dx.doi.org/10.1038/nsmb.2051 | DOI Listing |
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