{"doi":"10.1074/jbc.275.5.3412","title":"Functional Mapping of Receptor Specificity Domains of Glial Cell Line-derived Neurotrophic Factor (GDNF) Family Ligands and Production of GFRα1 RET-specific Agonists","abstract":null,"journal":"Journal of Biological Chemistry","year":2000,"id":590334,"datarank":4.027489028939465,"base_score":4.174387269895637,"endowment":4.174387269895637,"self_citation_contribution":0.6261580904843456,"citation_network_contribution":3.401330938455119,"self_endowment_contribution":0.6261580904843456,"citer_contribution":3.401330938455119,"corpus_percentile":null,"corpus_rank":null,"citation_count":64,"citer_count":59,"citers_with_citation_signal":51,"citers_with_endowment":51,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":77489,"name":"Malú G. Tansey","orcid":"0000-0002-1719-4708","position":1,"is_corresponding":false},{"id":170374,"name":"Eugene M. Johnson","orcid":null,"position":2,"is_corresponding":false},{"id":240472,"name":"Jeffrey Milbrandt","orcid":"0000-0002-5477-7689","position":3,"is_corresponding":false},{"id":235130,"name":"Robert H. Baloh","orcid":"0000-0002-0100-8376","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Functional Mapping of Receptor Specificity Domains of Glial Cell Line-derived Neurotrophic Factor (GDNF) Family Ligands and Production of GFRα1 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.","is_dataset_classified":null,"base_score":4.174387269895637,"endowment":4.174387269895637,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"10652334","pmcid":null,"openalex_id":"https://openalex.org/W2070905088","authors":[],"funders":[{"funder_name":"NIA NIH HHS","grant_id":"R01 AG13729","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R01 AG13730","title":null}],"total_grants":2,"fwci":1.4239,"citation_percentile":0.79894277,"influential_citations":0,"citation_trend":[{"year":2012,"count":4},{"year":2013,"count":2},{"year":2014,"count":2},{"year":2015,"count":3},{"year":2016,"count":2},{"year":2017,"count":1},{"year":2018,"count":1},{"year":2019,"count":1}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1074/jbc.275.5.3412","host_type":"journal"},{"url":"https://doi.org/10.1074/jbc.275.5.3412","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925818309232?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925818309232?httpAccept=text/plain","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1074/jbc.275.5.3412","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/10652334","host_type":"repository"},{"url":"http://www.jbc.org/content/275/5/3412.full.pdf","host_type":"Unpaywall"},{"url":"http://www.jbc.org/article/S0021925818309232/pdf","host_type":"Unpaywall"}],"fields_of_study":["Nerve injury and regeneration","Signaling Pathways in Disease","Neurogenesis and neuroplasticity mechanisms","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","Nerve Tissue Proteins","Proto-Oncogene Proteins","Proto-Oncogene Proteins c-ret","Receptor Protein-Tyrosine Kinases","Signal Transduction"],"mesh_terms":["Amino Acid Sequence","Animals","Binding Sites","Ligands","Molecular Sequence Data","Nerve Growth Factors","Nerve Tissue Proteins","Proto-Oncogene Proteins","Signal Transduction","Mutagenesis, Site-Directed","3T3 Cells","Receptor Protein-Tyrosine Kinases","Drosophila Proteins","Proto-Oncogene Proteins c-ret","Glial Cell Line-Derived Neurotrophic Factor Receptors","Glial Cell Line-Derived Neurotrophic Factor","Mice"],"keywords":["Glial cell line-derived neurotrophic factor","Neurturin","GDNF family of ligands","Proto-Oncogene Proteins c-ret","Neurotrophic factors","Biology","Neuroscience","Receptor","Dopaminergic","Cell biology","Receptor tyrosine kinase","Signal transduction","Genetics","Dopamine"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-24T17:40:18.582599Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}