Abstract
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.
Highlights
Members of the glial cell line-derived neurotrophic factor (GDNF)3 family regulate cell survival, differentiation, and migration in the peripheral and central nervous systems as well as in a few peripheral organs
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)
Signaling by GDNF family ligands is mediated by alternative multicomponent receptor complexes containing a ligand binding, glycosylphosphatidylinositol-anchored subunit termed GDNF family receptor ␣ (GFR␣) (4 –9), together with either the RET receptor tyrosine kinase [10, 11] or the neural cell adhesion molecule (NCAM) [12] as signaling subunits
Summary
Domain boundaries in the rat NCAM140 cDNA (Entrez ID X06564) [29] were defined based on the exon-intron structure of the chicken Ncam gene (Entrez ID AH005321) [30]. The boundaries used for generation of Ncam deletion constructs were as follows (numbering refers to the mature protein, excluding the 19-residue signal peptide): domain 1, Leu1-Gln; domain 2, Lys98-Val191; domain 3, Pro192-Ala288; domain 4, VOLUME 282 NUMBER 17 APRIL 27, 2007
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