Deducing Functional Epitopes for GDNF Proteins and Its Specific
GFRα Co-receptors Using Phylogenetic Approach

ZHANG Qing, WANG Li-Mei¹, CHEN Zhe-Yu¹, DING Da-Fu*

( Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences,
the Chinese Academy of Sciences, Shanghai 200031, China;
¹ Department of Neurobiology, the Second Military Medical University, Shanghai 200433, China )

Abstract Glial cell line-derived neurotrophic factor (GDNF) has received much attention as potential therapeutic agent for the treatment of neurodegenerative diseases. It will be very important to discover the molecular mechanism of this factor and its specific GFRa co-receptor. Based on the principle of molecular evolution that site-specific functional importance is relevant to the pressure it undergoes under natural selection, evolutionary trace method was used to identify the functional epitopes in GDNF and GFRa families. Some trace residues had been proved to be important in ligand-receptor binding, especially in rat GFRa1, where alanine scanning mutagenesis confirmed that sites N152N153, R259, S316N317S318 and Q247D248S249 were critical for GFRa1 binding to GDNF or Ret and thus affected the formation of GDNF-GFRa1-Ret complex.

Key words glial cell line-derived neurotrophic factor (GDNF) family; GFRa family; TGF-b super family; functional epitope; evolutionary trace

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