Editors' ChoiceNeurobiology

A Signaling Threesome

Science's STKE  11 May 2004:
Vol. 2004, Issue 232, pp. tw171-TW171
DOI: 10.1126/stke.2322004TW171

The neurotrophins are secreted growth factors that play a range of roles in the development and maintenance of the vertebrate nervous system through binding to two classes of receptors, the shared p75 neurotrophin receptor and the Trk receptor tyrosine kinase. Neurotrophins exist as dimers, and a crystal structure of the neurotrophin, nerve growth factor (NGF), bound to a ligand-binding domain of Trk has a 2:2 complex, which suggests that receptor dimerization may be involved in the activation mechanism. Now He and Garcia (see the Perspective by Zampieri and Chao) have determined the structure of NGF bound to the extracellular domain of p75 at 2.4 Å resolution. In the structure, an NGF dimer is bound to a single p75 monomer, and this allosteric binding prevents binding of a second p75. Signaling may thus occur through the disassembly of p75 dimers, which would potentially allow NGF-p75 complexes to engage the Trk receptor and to modulate its signaling.

X. He, K. C. Garcia, Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science 304, 870-875 (2004). [Abstract] [Full Text]

N. Zampieri, M. V. Chao, The p75 NGF receptor exposed. Science 304, 833-834 (2004). [Summary] [Full Text]