INP, a novel N-cadherin antagonist targeted to the amino acids that flank the HAV motif

Mol Cell Neurosci. 2000 May;15(5):456-64. doi: 10.1006/mcne.2000.0847.

Abstract

The classical cadherins are homophilic binding molecules that play fundamental roles in several biological processes, including axonal growth and synaptic plasticity. The structures of the amino-terminal homophilic binding domains of N-cadherin and E-cadherin have been resolved. However, the mechanisms that govern cadherin binding and specificity remain contentious. In the present study we have used a peptide competition approach to probe for small linear determinants of cadherin binding. We demonstrate that a linear peptide mimetic of a short sequence in ECD1 of N-cadherin (INPISGQ) functions as a highly specific and potent antagonist of N-cadherin function with an IC(50) value of approximately 15 microM. Peptide mimetics of the corresponding motif in chick R-cadherin also inhibited N-cadherin function, albeit with lower efficacy. In contrast, peptide mimetics of the corresponding motif in E- or P-cadherin failed to inhibit N-cadherin function. A short cyclic peptide that contained only the INP motif from N-cadherin was also a potent N-cadherin antagonist (IC(50) approximately 15 microM). Analysis of existing crystal structures suggests that the peptides are likely to antagonize N-cadherin function by binding to the region that flanks the HAV motif at the adhesion dimer interface.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Motifs*
  • Animals
  • Cadherins / chemistry
  • Cadherins / genetics*
  • Cadherins / metabolism*
  • Cells, Cultured
  • Chick Embryo
  • Crystallography
  • Fibroblast Growth Factors / metabolism
  • Humans
  • Leukocyte L1 Antigen Complex
  • Membrane Glycoproteins / metabolism
  • Mice
  • Molecular Conformation
  • Neural Cell Adhesion Molecules / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Rats

Substances

  • Cadherins
  • Leukocyte L1 Antigen Complex
  • Membrane Glycoproteins
  • Neural Cell Adhesion Molecules
  • Peptide Fragments
  • Peptides, Cyclic
  • R-cadherin
  • Fibroblast Growth Factors