Structural biology of NCAM homophilic binding and activation of FGFR

• Published in: Journal of neurochemistry 2005-09, Vol.94 (5), p.1169-1179
• Main Authors: Kiselyov, Vladislav V., Soroka, Vladislav, Berezin, Vladimir, Bock, Elisabeth
• Format: Article
• Language: English
• Subjects: Aminoacid receptors (glycine, glutamate, gaba); Anatomical correlates of behavior; Animals; Behavioral psychophysiology; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Cell Membrane - metabolism; Cell receptors; Cell structures and functions; Dimerization; fibroblast growth factor receptor activator; Fundamental and applied biological sciences. Psychology; homophilic binding mechanism; Molecular and cellular biology; neural cell adhesion molecule structure; Neural Cell Adhesion Molecules - chemistry; Neural Cell Adhesion Molecules - metabolism; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Receptors, Fibroblast Growth Factor - metabolism; signal transduction; Stereoisomerism
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03284.x

Summary In this review, we analyse the structural basis of the homophilic interactions of the neural cell adhesion molecule (NCAM) and the NCAM‐mediated activation of the fibroblast growth factor receptor (FGFR). Recent structural evidence suggests that NCAM molecules form cis‐dimers in the cell membrane through a high affinity interaction. These cis‐dimers, in turn, mediate low affinity trans‐interactions between cells via formation of either one‐ or two‐dimensional ‘zippers’. We provide evidence that FGFR is probably activated by NCAM very differently from the way by which it is activated by FGFs, reflecting the different conditions for NCAM–FGFR and FGF–FGFR interactions. The affinity of FGF for FGFR is approximately 106 times higher than that of NCAM for FGFR. Moreover, in the brain NCAM is constantly present on the cell surface in a concentration of about 50 µm, whereas FGFs only appear transiently in the extracellular environment and in concentrations in the nanomolar range. We discuss the structural basis for the regulation of NCAM–FGFR interactions by two molecular ‘switches’, polysialic acid (PSA) and adenosine triphosphate (ATP), which determine whether NCAM acts as a signalling or an adhesion molecule.