1. National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China
2. These authors contributed equally to this work.

Correspondence to: Tao Jiang¹ Correspondence and requests for materials should be addressed to T.J. (Email: tjiang@ibp.ac.cn).

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 (p75^NTR) and tyrosine kinase receptors (Trks). Whereas p75^NTR binds to all NTs, the Trk subtypes are specific for each NT^{1, 2}. The question of whether NTs stimulate p75^NTR 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 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.

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