Direct Evidence That Neural Cell Adhesion Molecule (NCAM) Polysialylation Increases Intermembrane Repulsion and Abrogates Adhesion

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2005; 280(1):137-45. DOI: 10.1074/jbc.M410216200
Source: PubMed


Molecular force measurements quantified the impact of polysialylation on the adhesive properties both of membrane-bound neural cell adhesion molecule (NCAM) and of other proteins on the same membrane. These results show quantitatively that NCAM polysialylation increases the range and magnitude of intermembrane repulsion. The repulsion is sufficient to overwhelm both homophilic NCAM and cadherin attraction at physiological ionic strength, and it abrogates the protein-mediated intermembrane adhesion. The steric repulsion is ionic strength dependent and decreases substantially at high monovalent salt concentrations with a concomitant increase in the intermembrane attraction. The magnitude of the repulsion also depends on the amount of polysialic acid (PSA) on the membranes, and the PSA-dependent attenuation of cadherin adhesion increases with increasing PSA-NCAM:cadherin ratios. These findings agree qualitatively with independent reports based on cell adhesion studies and reveal the likely molecular mechanism by which NCAM polysialylation regulates cell adhesion and intermembrane space.

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Available from: Deborah E Leckband
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    • "This unique glycosylation is attached mainly to the neural cell-adhesion molecule (NCAM) (62), which is expressed on cells of neuroectodermal origin and plays a pivotal role in neural tissue development and regeneration. It is well documented that the presence of the highly negatively charged PSA on NCAM reduces NCAM-mediated adhesion processes as well as NCAM-independent cell interactions, such as cadherin-mediated cell-adhesion (63, 64). There are several isoforms of NCAM due to different sizes, three of which can carry PSA: NCAM-180 and NCAM-140 (integral membrane isoforms), and NCAM-120 (isoform anchored to the plasma membrane via a glycosyl phosphoinositol) (65, 66). "
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    • "Their degree of polymerization (DP), or chain length, can exceed 400 Sia residues when accurately determined in the absence of acid hydrolysis [6] [7]. Thus, polySia is a large polyanionic ''space filling'' molecule that functions as an anti-adhesive glycan on cell–cell and cell– matrix interactions [7] [8] [9] [10]. "
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    • "Finally, the shielding effect of sialic acid could also be explained by the repulsive forces induced by the negative charge of sialic acid. For example, sialylation of endothelial cells in developing blood vessels has been shown to create repulsion able to initiate lumen formation [46], and polysialylation of neural cell adhesion molecules increases intermembrane repulsion [47], [48]. Taken together, these observations suggest that removal of sialic acid could also render cancer cells more prone to NK cell-mediated killing. "
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