Extracellular Binding Partners of NCAM

The domains involved in homophilic NCAM-NCAM recognition remain a matter of debate. Early data suggested antiparallel association of the five Ig-like domains of one molecule with five Ig-like domains of another NCAM molecule5, with the highest affinity found in that between the third Ig-like domains. More recently, an interaction involving the first two Ig-like domains has been put forward6. Additionally, more complex models of trans--interaction between dimers of cis-interacting NCAM molecules have been proposed on the basis of crystal structure of the first three NCAM Ig domains (reviewed in ref. 7). However, two recent studies using surface force apparatus and atomic force microscopy8,9 have suggested that NCAM preferentially adheres in two fashions: either in a fully, antiparallel alignment requiring Ig3, or in a separate, weaker antiparallel interaction between the Ig1-Ig2 domains.

Figure 6.1. Structure of NCAM and PSA. The extracellular domain of NCAM contains five Ig-like subdomains (semicircles) and two FNIII repeats (rectangles). Glycosylation sites are indicated by black spots; two numbered sites indicate amino acid positions to which PSA may be attached. Several NCAM-binding proteins are listed around NCAM. PSA (on the right) is found on di- and triantennary A-glycan chains attached to at least two N-glycosylation sites within the fifth Ig-like domain of all three NCAM isoforms. A large number of a2,8-linked sialic acid residues (empty triangles) are found attached to one antenna through a2,3-linked sialic acid (empty circles). A-acetylglucosamine and mannose residues are shown as filled squares and circles, respectively. For more details, see ref. 10.

NCAM is also engaged in a number of heterophilic interactions. The fourth Ig-like domain of NCAM contains a carbohydrate recognition site for oligomannosidic glycans that is important for its cis-association with another adhesion molecule, termed L1. This cis-interaction has been suggested to enhance the homophilic trans-binding of L111. Using short synthetic peptides, a heterophilic-binding region for heparin, consisting of two clusters of basic amino acid residues, has been allocated to the second Ig-like domain of NCAM12. Structural analysis suggests that the heparin and chondroitin sulfate-binding sites in Ig2 coincide, and that this site overlaps with the homophilic-binding site13. Other extracellular ligands of NCAM are neurocan and phosphacan14, soluble nervous tissue-specific chondroitin sulfate proteoglycans (CSPGs). The FGF receptor is another major binding partner of NCAM15. Interaction between molecules may involve a direct interaction between the first two fibronectin type III domains of NCAM and the Ig2 and Ig3 immunoglobulin domains of the FGF receptor7. NCAM also associates with GFR1, a GPI-anchored receptor for GDNF. This interaction downregulates NCAM-mediated cell adhesion and promotes high-affinity binding of GDNF to NCAM 140, resulting in rapid activation of the cytoplasmic protein tyrosine kinases, fyn and FAK16. Among other binding partners of NCAM are prion protein, TAG-1/axonin-1, and collagens.

As mentioned above, presence of PSA on NCAM inhibits NCAM-NCAM mediated interactions. PSA also inhibits adhesive interactions mediated by L1, cadherins, and integrins17, and thus appears as a rather universal inhibitor of adhesion. Recent molecular force measurements directly show that NCAM polysialylation increases the range and magnitude of intermembrane repulsion18. On the other hand, PSA promotes binding between HSPGs and the NCAM heparin-binding domain19, as well as signaling mediated by brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF), and glutamate receptors20-22. Thus, polysialylation of NCAM may function as a 'switch,' determining whether NCAM is engaged in cell adhesion or in signaling.

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