Functional mapping of receptor specificity domains of glial cell line-derived neurotrophic factor (GDNF) family ligands and production of GFRalpha1 RET-specific agonists.

Abstract	The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) (GDNF, neurturin, artemin, and persephin) are critical regulators of neurodevelopment and support the survival of midbrain dopaminergic and spinal motor neurons in vitro and in animal disease models making them attractive therapeutic candidates for treatment of neurodegenerative diseases. The GFLs signal through a multicomponent receptor complex comprised of a high affinity binding component (GDNF-family receptor alpha-component (GFRalpha1-GFRalpha4)) and the receptor tyrosine kinase RET. To begin characterization of GFL receptor specificity at the molecular level, we performed comprehensive homologue-scanning mutagenesis of GDNF, the prototypical member of the GFLs. Replacing short segments of GDNF with the homologous segments from persephin (PSPN) (which cannot bind or activate GFRalpha1.RET or GFRalpha2.RET) identified sites along the second finger of GDNF critical for activating the GFRalpha1.RET and GFRalpha2.RET receptor complexes. Furthermore, introduction of these regions from GDNF, neurturin, or artemin into PSPN demonstrated that they are sufficient for activating GFRalpha1. RET, but additional determinants are required for interaction with the other GFRalphas. This difference in the molecular basis of GFL-GFRalpha specificity allowed the production of GFRalpha1. RET-specific agonists and provides a foundation for understanding of GFL-GFRalpha.RET signaling at the molecular level.
Authors	R H Baloh, M G Tansey, E M Johnson Jr, J Milbrandt
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 5 Pg. 3412-20 (Feb 04 2000) ISSN: 0021-9258 [Print] United States
PMID	10652334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Drosophila Proteins Gdnf protein, mouse Gfra1 protein, mouse Gfra2 protein, mouse Glial Cell Line-Derived Neurotrophic Factor Glial Cell Line-Derived Neurotrophic Factor Receptors Ligands Nerve Growth Factors Nerve Tissue Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-ret Receptor Protein-Tyrosine Kinases Ret protein, Drosophila Ret protein, mouse
Topics	3T3 Cells Amino Acid Sequence Animals Binding Sites Drosophila Proteins Glial Cell Line-Derived Neurotrophic Factor Glial Cell Line-Derived Neurotrophic Factor Receptors Ligands Mice Molecular Sequence Data Mutagenesis, Site-Directed Nerve Growth Factors (chemistry, genetics, metabolism) Nerve Tissue Proteins (chemistry, genetics, metabolism) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-ret Receptor Protein-Tyrosine Kinases (metabolism) Signal Transduction

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