INP, a novel N-cadherin antagonist targeted to the amino acids that flank the HAV motif.
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.
Williams
E J
EJ
The Molecular Neurobiology Group, King's College, London, United Kingdom.
Williams
G
G
Gour
B
B
Blaschuk
O
O
Doherty
P
P
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
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