Mechanism of Homophilic Adhesion by the Neural Cell Adhesion Molecule: Use of Multiple Domains and Flexibility

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 18; pp. 6963 - 6968
• Main Authors: Johnson, C. P., Fujimoto, I., Perrin-Tricaud, C., Rutishauser, U., Leckband, D., Schowalter, William R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04-05-2004; National Acad Sciences
• Subjects: Adhesion; Adhesive bonding; Adhesives; Amino acids; Animals; Biological Sciences; Biophysics; Cell adhesion; Cell Adhesion - physiology; Chemical bonding; CHO Cells; Cricetinae; Lipid Bilayers - metabolism; Lipids; Modeling; Neural cell adhesion molecules; Neural Cell Adhesion Molecules - metabolism; Protein Structure, Tertiary; Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0307567100

The extracellular regions of adhesion proteins of the Ig superfamily comprise multiple, tandemly arranged domains. We used direct-force measurements to investigate how this modular architecture contributes to the adhesive interactions of the neural cell adhesion molecule (NCAM), a representative of this protein class. The extracellular region of NCAM comprises five immunoglobulin and two fibronectin domains. Previous investigations generated different models for the mechanism of homophilic adhesion that each use different domains. We use force measurements to demonstrate that NCAM binds in two spatially distinct configurations. Ig-domain deletion mutants identified the domains responsible for each of the adhesive bonds. The measurements also confirmed the existence of a flexible hinge that alters the orientation of the adhesive complexes and the intermembrane distance. These results suggest that a combination of multiple bound states and internal molecular flexibility allows for sequentially synergistic bond formation and the ability to accommodate differences in intercellular space.