[Deducing functional epitopes for GDNF proteins and its specific GFRalpha co-receptors using phylogenetic approach].
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 GFRalpha 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 GFRalpha families. Some trace residues had been proved to be important in ligand-receptor binding, especially in rat GFRalpha1, where alanine scanning mutagenesis confirmed that sites N(152)N(153), R(259), S(316)N(317)S(318) and Q(247)D(248)S(249) were critical for GFRalpha1 binding to GDNF or Ret and thus affected the formation of GDNF-GFRalpha1-Ret complex.
Zhang
Qing
Q
Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, the Chinese Academy of Sciences, Shanghai 200031, China. dingdafu@server.shcnc.ac.cn
Wang
Li-Mei
LM
Chen
Zhe-Yu
ZY
Ding
Da-Fu
DF
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009414:Nerve Growth Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism
D000939:Epitopes; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C495001:Ret protein, rat