Axonin-1/TAG-1 mediates cell-cell adhesion by a cis-assisted trans-interaction.
The neural cell adhesion molecule axonin-1/TAG-1 mediates cell-cell interactions via homophilic and heterophilic contacts. It consists of six Ig and four fibronectin type III domains anchored to the membrane by glycosylphosphatidylinositol. The recently solved crystal structure indicates a module composed of the four N-terminal Ig domains as the contact site between trans-interacting axonin-1 molecules from apposed membranes. Here, we have tested domain-specific monoclonal antibodies for their capacity to interfere with homophilic binding in a cell aggregation assay. The results confirmed the existence of a binding region within the N-terminal Ig domains and identified a second region contributing to homophilic binding on the third and fourth fibronectin domains near the C terminus. The perturbation of each region alone resulted in a complete loss of cell aggregation, suggesting that axonin-1-mediated cell-cell contact results from a cooperative action of two homophilic binding regions. The data support that axonin-1-mediated cell-cell contact is formed by cis-assisted trans-binding. The N-terminal binding regions of axonin-1 establish a linear zipper-like string of trans-interacting axonin-1 molecules alternately provided by the two apposed membranes. The C-terminal binding regions strengthen the cell-cell contact by enhancing the expansion of the linear string into a two-dimensional array via cis-interactions. Cis-assisted trans-binding may be a basic binding mechanism common to many cell adhesion molecules.
Kunz
Beat
B
Institute of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.
Lierheimer
Ruth
R
Rader
Christoph
C
Spirig
Marianne
M
Ziegler
Urs
U
Sonderegger
Peter
P
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002642:Chick Embryo; D058969:Contactin 2; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding
D015816:Cell Adhesion Molecules, Neuronal; C548675:Cntn2 protein, mouse; D058969:Contactin 2