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

The classical cadherins are hemophilic binding molecules that play fundamen tal roles in several biological processes, including axonal growth and syna ptic plasticity. The structures of the amino-terminal hemophilic binding do mains of N-cadherin and E-cadherin have been resolved. However, the mechani sms that govern cadherin binding and specificity remain contentious. In the present study we have used a peptide competition approach to probe for sma ll linear determinants of cadherin binding. We demonstrate that a linear pe ptide 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 IC50 value of similar to 15 mu M. Peptide mimetics of the corresponding mot if in chick R-cadherin also inhibited N-cadherin function, albeit with lowe r 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-cadh erin antagonist (IC50 similar to 15 mu M). Analysis of existing crystal str uctures suggests that the peptides are likely to antagonize N-cadherin func tion by binding to the region that flanks the HAV motif at the adhesion dim er interface.