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Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex

Nature volume 454, pages 789–793 (2008)Cite this article

Abstract

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 (p75NTR) and tyrosine kinase receptors (Trks). Whereas p75NTR binds to all NTs, the Trk subtypes are specific for each NT1,2. The question of whether NTs stimulate p75NTR by inducing receptor homodimerization is still under debate. Here we report the 2.6-Å resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75NTR. 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 p75NTR (ref. 3), we show that NT-3 forms a central homodimer around which two glycosylated p75NTR 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 p75NTR conformations. Biochemical experiments indicate that both NT-3 and NGF bind to p75NTR 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 p75NTR activation at the cell surface. These results provide a model for NTs-p75NTR recognition and signal generation, as well as insights into coordination between p75NTR and Trks.

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Figure 1: Architecture of the NT-3–p75 NTR complex.
Figure 2: Interactions between p75 NTR and NT-3.
Figure 3: Structural comparison.
Figure 4: Comparison of the 2:2 NT-3–p75 NTR complex with the 2:1 NGF–dg-p75 NTR complex.

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Protein Data Bank

Data deposits

Atomic coordinates and structure factors have been deposited in the Protein Data Bank under accession code 3BUK.

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Acknowledgements

We thank X. X. Yu for help with analytical ultracentrifugation assay, and Y. Y. Chen for the BIAcore assay. We thank Genentech for the gift of recombinant human NT-3 and recombinant human NGF. This research was supported financially by the National Key Basic Research Program, the National Natural Science Foundation of China and the National High Technology Research and Development Program of China.

Author Contributions T.J. supervised the project. Y.G. expressed, purified and crystallized the complex and performed biochemical assays. P.C. determined the structure of the complex. H.J.Y. helped with its expression and purification. P.C., Y.G. and T.J. interpreted data and wrote the paper.

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  1. Yong Gong and Peng Cao: These authors contributed equally to this work.

Authors and Affiliations

  1. National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China ,

    Yong Gong, Peng Cao, Hong-jun Yu & Tao Jiang

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  1. Yong Gong
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Correspondence to Tao Jiang.

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Gong, Y., Cao, P., Yu, Hj. et al. Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex. Nature 454, 789–793 (2008). https://doi.org/10.1038/nature07089

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