A conserved Neurite Outgrowth and Guidance motif with biomimetic potential in neuronal Cell Adhesion Molecules

Abstract

Graphical abstract The extracellular domains of several neuronal Cell Adhesion Molecules (CAMs) are endowed with Ig-like fold (Ig, hexagons) and fibronectin-like III (FnIII, pentagons) repeats. Such CAMs mediate homo- and heterophilic interactions crucial for neurite outgrowth and guidance (NOG). The Ig2 domains of these CAMs share a specific and highly conserved NOG motif, bioinformatically represented by a Prosite pattern. Developed synthetic peptides derived from the NOG motif are able to mimic the pro-neuritogenic activities of CAMs they are derived from and hence can be used as a toolbox for neurodevelopmental studies and regenerative medicine.

NOG-Derived Peptides Can Restore Neuritogenesis on a CRASH Syndrome Cell Model

“…L1-A derives from the NOG motif of L1CAM, and it is suggested to mimic the homophilic binding of its extracellular domain (L1CAM ED) [ 17 ]. Moreover, all NOG-derived peptides have recently proven to enhance neuritogenesis in cell culture, possibly by binding to the ectodomains of a number of neuronal CAMs [ 22 ]. As peptides and L1CAM ED can trigger the same process, we wondered if some difference could be observed between them in terms of neuritogenic efficacy.…”

“…Similarly, mutation L1CAM_R184Q, which is associated with a severe form of the CRASH syndrome, also strongly impaired neuritogenesis, which, instead, was only partially diminished by mutation I179S, in agreement with its association with a milder CRASH phenotype [ 45 ]. Intriguingly, in the regular expression representing relative conservation of residues in the NOG motif, R184 corresponds to position 7, where only Arg is accepted (100% conservation in an almost ten thousands CAMs dataset), whereas I179 corresponds to position 2, where both Ile and Ser are among accepted residues [ 22 ]. Overall, data confirm that when the Ig2 binding site is altered by mutation, the neuritogenic capacity of L1CAM can be diminished or even lost.…”

“…This region has recently been found to be part of a Neurite Outgrowth and Guidance (NOG) motif, which is 100% conserved in mammals and man among roughly ten thousand of neuronal CAMs, including all four members of the L1 family proteins (L1CAM, Close Homolog of L1 or CHL1, NrCAM, and Neurofascin), Contactins, Deleted in Colon Carcinoma (DCC)/Netrin receptor and Roundabout (ROBO) receptors [ 22 ]. In such proteins, the NOG region is part of a beta-hairpin loop stabilized by a salt bridge between a fully conserved arginine and aspartic acid residue.…”

“…Synthetic peptides derived from the NOG motifs of these CAMs are unstructured and stable for at least 48 h in culture media. Most importantly, they all share proneuritogenic capacity and have been found to bind L1CAM ectodomain in competition surface plasmon resonance assays [ 22 ].…”

“…Several CRASH-causing mutations fall into the NOG region of L1CAM, and interestingly the R184Q mutation hampers the fully conserved arginine of the NOG motif [ 22 ]. This prompted us to set up a model system to evaluate the effect of such mutations on neuritogenesis and to exploit the potential of biomimetic peptides as either negative or positive regulators.…”