Insight into the structural mechanism of the bi-modal action of an NCAM mimetic, the C3 peptide

C3, a synthetic peptide binding to the Ig1 module of the neural cell adhesion molecule (NCAM) has previously been identified and shown to inhibit NCAM homophilic binding and NCAM-mediated activation of the fibroblast growth factor (FGF) receptor (FGFR). However, C3 can also stimulate signalling on its own in a way similar to NCAM. Here we show that in the absence of NCAM, C3 can bind and activate FGFR, whereas in the presence of NCAM, C3 inhibits the NCAM-stimulated FGFR activation without activating FGFR on its own. Several competing models of FGFR activation by NCAM have been previously proposed. In one of them, the FGFR Ig2–Ig3 modules are involved in binding to NCAM, whereas in another – the FGFR “acid box” region mediates the interaction. The bi-modal effect of C3 can be explained in the context of the former model and is not consistent with the latter, thus providing evidence in support of the former model.