Molecular Design Principles Underlying beta-strand Swapping in the Adhesive Dimerization of Cadherins

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Nature Structural and Molecular Biology

DOI:https://doi.org/10.1038/nsmb.2051· OSTI ID:1041960

Vendome, J; Posy, S; Jin, X; Bahna, F; Ahlsen, G; Shapiro, L; Honig, B

Cell adhesion by classical cadherins is mediated by dimerization of their EC1 domains through the 'swapping' of N-terminal {beta}-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{sup 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.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1041960
• Report Number(s): BNL--97638-2012-JA
• Journal Information: Nature Structural and Molecular Biology, Journal Name: Nature Structural and Molecular Biology Journal Issue: 6 Vol. 18; ISSN 1545-9993
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ADHESION
ADHESIVES
AFFINITY
CRYSTALLOGRAPHY
DESIGN
DIMERIZATION
FASTENING
MONOMERS
MUTATIONS
STRAINS