title: INP, a novel N-cadherin antagonist targeted to the amino acids that flank the HAV motif.
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.
authors.affiliation: The Molecular Neurobiology Group, King's College, London, United Kingdom.
authors.forename: E J
authors.initials: EJ
authors.lastname: Williams
authors.forename: G
authors.initials: G
authors.lastname: Williams
authors.forename: B
authors.initials: B
authors.lastname: Gour
authors.forename: O
authors.initials: O
authors.lastname: Blaschuk
authors.forename: P
authors.initials: P
authors.lastname: Doherty
mesh_terms: D016475:3T3 Cells; D020816:Amino Acid Motifs; D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D003461:Crystallography; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008968:Molecular Conformation; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D015820:Cadherins; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C083970:R-cadherin; D005346:Fibroblast Growth Factors