Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex
Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex
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DOI：
10.1038/nature07089
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发表时间：
2008-08-07
期刊：
影响因子：
64.8
通讯作者：
Jiang, Tao
中科院分区：
文献类型：
--
作者：
Gong, Yong;Cao, Peng;Jiang, Tao
神经营养因子(NTS)是不同外周和中枢神经元存活、分化和维持的重要调节因子。NTS与两类不同类型的糖基化受体结合：p75神经营养素受体(p75(NTR))和酪氨酸激酶受体(Trks)。虽然p75(NTR)与所有NTS结合，但Trk亚型对每个NT1是特定的。2.NTS是否通过诱导受体同源二聚化来刺激p75(NTR)的问题仍在争论中。在这里，我们报道了神经营养素-3(NT-3)与糖基化p75(NTR)胞外结构域的2.6埃分辨率的晶体结构。与先前报道的不对称复杂结构相反，该结构包含一个神经生长因子(NGF)二聚体，与脱糖基化的p75(NTR)的单个胞外结构域结合(参考文献.3)，我们证明了NT-3形成了一个中心同源二聚体，两个糖基化的p75(NTR)分子对称地结合在这个中心二聚体周围。沿着NT-3界面发生对称结合，导致2：2的配体-受体簇。对对称和不对称结构的比较表明，在配体受体相互作用和p75(NTR)构象方面存在显著差异。生化实验表明，NT-3和NGF在溶液中以2：2的化学计量比与p75(NTR)结合，而2：1的复合体是人工去糖基化的结果。因此，我们认为对称的2：2复合体反映了细胞表面p75(NTR)激活的自然状态。这些结果为NTS-p75(NTR)的识别和信号生成提供了一个模型，也为p75(NTR)和Trks之间的协调提供了见解。
Neurotrophins (NTs) are important regulators for the survival, differentiation and maintenance of different peripheral and central neurons. NTs bind to two distinct classes of glycosylated receptor: the p75 neurotrophin receptor (p75(NTR)) and tyrosine kinase receptors (Trks). Whereas p75(NTR) binds to all NTs, the Trk subtypes are specific for each NT1,2. The question of whether NTs stimulate p75(NTR) by inducing receptor homodimerization is still under debate. Here we report the 2.6-angstrom resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75(NTR). In contrast to the previously reported asymmetric complex structure, which contains a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75(NTR) (ref. 3), we show that NT-3 forms a central homodimer around which two glycosylated p75(NTR) molecules bind symmetrically. Symmetrical binding occurs along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand receptor interactions and p75(NTR) conformations. Biochemical experiments indicate that both NT-3 and NGF bind to p75(NTR) with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. We therefore propose that the symmetrical 2:2 complex reflects a native state of p75(NTR) activation at the cell surface. These results provide a model for NTs-p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and Trks.