Wang Xinquan, Baloh Robert H, Milbrandt Jeffrey, Garcia K Christopher
Howard Hughes Medical Institute, Stanford University School of Medicine, Department of Microbiology and Immunology, Stanford, California 94305-5124, USA.
Structure. 2006 Jun;14(6):1083-92. doi: 10.1016/j.str.2006.05.010.
Artemin (ARTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) which regulate the development and maintenance of many neuronal populations in the mammalian nervous system. Here we report the 1.92 A crystal structure of the complex formed between ARTN and its receptor GFRalpha3, which is the initiating step in the formation of a ternary signaling complex containing the shared RET receptor. It represents a new receptor-ligand interaction mode for the TGF-beta superfamily that reveals both conserved and specificity-determining anchor points for all GFL-GFRalpha pairs. In tandem with the complex structure, cellular studies using receptor chimeras implicate dyad-symmetric composite interfaces for recruitment and dimerization of RET, leading to intracellular signaling. These studies should facilitate the functional dissection of the specific versus pleiotropic roles of this system in neurobiology, as well as its exploitation for therapeutic applications.
Artemin（ARTN）是胶质细胞系衍生神经营养因子（GDNF）家族配体（GFLs）的成员，该家族配体调节哺乳动物神经系统中许多神经元群体的发育和维持。在此，我们报道了ARTN与其受体GFRalpha3形成的复合物的1.92埃晶体结构，这是形成包含共享RET受体的三元信号复合物的起始步骤。它代表了TGF-β超家族一种新的受体-配体相互作用模式，揭示了所有GFL-GFRalpha对的保守和决定特异性的锚定位点。与复合物结构一起，使用受体嵌合体的细胞研究表明，二元对称复合界面参与RET的募集和二聚化，从而导致细胞内信号传导。这些研究应有助于在神经生物学中对该系统的特异性与多效性作用进行功能剖析，以及将其用于治疗应用。
