利用系统发育方法推导胶质细胞源性神经营养因子（GDNF）蛋白及其特定GFRα共受体的功能性表位

[Deducing functional epitopes for GDNF proteins and its specific GFRalpha co-receptors using phylogenetic approach].

作者信息

Zhang Qing, Wang Li-Mei, Chen Zhe-Yu, Ding Da-Fu

机构信息

Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, the Chinese Academy of Sciences, Shanghai 200031, China.

出版信息

Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003 Apr;35(4):331-7.

PMID:12673386

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 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.

摘要

胶质细胞系源性神经营养因子（GDNF）作为治疗神经退行性疾病的潜在治疗剂受到了广泛关注。发现该因子及其特异性GFRα共受体的分子机制将非常重要。基于分子进化原理，即位点特异性功能重要性与其在自然选择下所承受的压力相关，采用进化追踪方法来鉴定GDNF和GFRα家族中的功能表位。一些追踪残基已被证明在配体-受体结合中很重要，特别是在大鼠GFRα1中，丙氨酸扫描诱变证实位点N(152)N(153)、R(259)、S(316)N(317)S(318)和Q(247)D(248)S(249)对于GFRα1与GDNF或Ret的结合至关重要，从而影响GDNF-GFRα1-Ret复合物的形成。