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Structure of Nerve Growth Factor Complexed with the Shared Neurotrophin Receptor p75
Xiao-lin He and
K. Christopher Garcia*
Neurotrophins are secreted growth factors critical for the developmentand maintenance of the vertebrate nervous system. Neurotrophinsactivate two types of cell surface receptors, the Trk receptortyrosine kinases and the shared p75 neurotrophin receptor. Wehave determined the 2.4 Å crystal structure of the prototypicneurotrophin, nerve growth factor (NGF), complexed with theextracellular domain of p75. Surprisingly, the complex is composedof an NGF homodimer asymmetrically bound to a single p75. p75binds along the homodimeric interface of NGF, which disablesNGF's symmetry-related second p75 binding site through an allostericconformational change. Thus, neurotrophin signaling throughp75 may occur by disassembly of p75 dimers and assembly of asymmetric2:1 neurotrophin/p75 complexes, which could potentially engagea Trk receptor to form a trimolecular signaling complex.
Departments of Microbiology and Immunology, and Structural Biology, Stanford University School of Medicine, Fairchild D319, 299 Campus Drive, Stanford, CA 94305–5124, USA.
* To whom correspondence should be addressed. E-mail: kcgarcia{at}stanford.edu
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