Disruption of the GDNF binding site in NCAM dissociates ligand binding and homophilic cell adhesion.
Most plasma membrane proteins are capable of sensing multiple cell-cell and cell-ligand interactions, but the extent to which this functional versatility is founded on their modular design is less clear. We have identified the third immunoglobulin domain of the Neural Cell Adhesion Molecule (NCAM) as the necessary and sufficient determinant for its interaction with Glial Cell Line-derived Neurotrophic Factor (GDNF). Four charged contacts were identified by molecular modeling as the main contributors to binding energy. Their mutation abolished GDNF binding to NCAM but left intact the ability of NCAM to mediate cell adhesion, indicating that the two functions are genetically separable. The GDNF-NCAM interface allows complex formation with the GDNF family receptor alpha1, shedding light on the molecular architecture of a multicomponent GDNF receptor.
Sjöstrand
Dan
D
Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, S-171 77 Stockholm, Sweden.
Carlsson
Jonas
J
Paratcha
Gustavo
G
Persson
Bengt
B
Ibáñez
Carlos F
CF
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002448:Cell Adhesion / Q000235:genetics; D002522:Chlorocebus aethiops; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D013329:Structure-Activity Relationship
D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D019006:Neural Cell Adhesion Molecules