A novel family of cyclic peptide antagonists suggests that N-cadherin specificity is determined by amino acids that flank the HAV motif.
The classical cadherins (e.g. N-, E-, and P- cadherin) are well established homophilic adhesion molecules; however, the mechanism that governs cadherin specificity remains contentious. The classical cadherins contain an evolutionarily conserved His-Ala-Val (HAV) sequence, and linear peptides harboring this motif are capable of inhibiting a variety of cadherin-dependent processes. We now demonstrate that short cyclic HAV peptides can inhibit N-cadherin function. Interestingly, the nature of the amino acids that flank the HAV motif determine both the activity and specificity of the peptides. For example, when the HAV motif is flanked by a single aspartic acid, which mimics the natural HAVD sequence of N-cadherin, the peptide becomes a much more effective inhibitor of N-cadherin function. In contrast, when the HAV motif is flanked by a single serine, which mimics the natural HAVS sequence of E-cadherin, it loses its ability to inhibit the N-cadherin response. Our results demonstrate that subtle changes in the amino acids that flank the HAV motif can account for cadherin specificity and that small cyclic peptides can inhibit cadherin function. An emerging role for cadherins in a number of pathological processes suggests that the cyclic peptides reported in this study might be developed as therapeutic agents.
Williams
E
E
Molecular Neurobiology Group, Guy's King's and St. Thomas' School of Medicine, King's College London, Guy's Campus, London SE1 9RT, United Kingdom.
Williams
G
G
Gour
B J
BJ
Blaschuk
O W
OW
Doherty
P
P
D016475:3T3 Cells; D000818:Animals; D001921:Brain / Q000378:metabolism; D015820:Cadherins / Q000737:chemistry / Q000235:genetics*; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D015820:Cadherins; D010456:Peptides, Cyclic