Nerve growth factor: structure and function

Neurotrophins are critical for the development and maintenance of the perip heral and central nervous system. These highly homologous, homodimeric grow th factors control cell survival, differentiation, growth cessation, and ap optosis of sensory neurons. The biological functions of the neurotrophins a re mediated through two classes of cell surface receptors, the Trk receptor s and the p75 neurotrophin receptor (p75(NTR)). Nerve growth factor (NGF), the best characterized member of the neurotrophin family, sends its surviva l signals through activation of TrkA and can induce cell death by binding t o p75(NTR) Recent domain deletion and mutagenesis studies have identified t he membrane-proximal domain of the Trks as necessary and sufficient for lig and binding. Crystal structures of this domain of TrkA, TrkB, and TrkC, and an alanine scanning analysis of this domain of TrkA and TrkC have allowed identification of the ligand-binding site. The recent crystal structure of the complex between NGF and the ligand-binding domain of TrkA defines the o rientation of NGF in the signaling complex, and eludicates the structural b asis for binding and specificity in the family. Further structural work on NGF-TrkA-p7S(NTR) complexes will be necessary to address the many remaining questions in this complex signaling system.