Structural determinants of neurotrophin action.
Five decades of research on NGF have led to the discovery of a small family of evolutionarily conserved proteins, which have vital functions in the survival and neuronal development of specific neuronal populations. The generation of mice lacking neurotrophin expression has recapitulated classic experiments using anti-NGF antibodies to dissect the physiological effects of trophic factor deprivation (73). Very similar outcomes resulted from both the NGF immunodepletion experiments and the transgenic mouse experiments. The genetic results also verify the structural predictions made from binding results in heterologous cells. The findings in cell culture and animal experiments clearly indicate the efficacy of neurotrophic factors for promoting the survival of prominent neuronal populations such as sensory and motor neurons. The high degree of conservation of neurotrophin structure is accompanied by a surprising variation in the amino acid contacts used by each neurotrophin with p75 and the trk receptor family members. It is this variation that may provide specificity for each ligand-receptor complex. The future challenge will be to make use of this knowledge to design effective therapeutic strategies to treat neurodegeneration and nerve injury.
McDonald
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NQ
ICRF Unit for Structural Molecular Biology, Department of Crystallography, Birkbeck College, London, United Kingdom.
Chao
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MV
D000818:Animals; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D015398:Signal Transduction
D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor