Emerging themes in structural biology of neurotrophic factors

doi:10.1016/S0166-2236(98)01266-1

Trends in Neurosciences

Volume 21, Issue 10, 1 October 1998, Pages 438-444

https://doi.org/10.1016/S0166-2236(98)01266-1 Get rights and content

Abstract

Neurotrophic factors control the survival, differentiation and maintenance of neurons in the peripheral and central nervous systems. Their discovery and characterization have been instrumental to our understanding of a wide range of phenomena in the development, plasticity and repair of the nervous system. Their potential importance in the development of therapeutic agents against neurodegenerative disorders and nerve injury has led to a flurry of activity towards understanding their structure, function and signaling mechanisms. This knowledge has increased dramatically in recent years, in particular due to the elucidation of three-dimensional structures, the discovery of families of structurally related neurotrophic factors and the characterization of receptors and downstream signaling components. Common themes are emerging from these recent studies that allow us to make new insights and predictions as to the function and possible clinical utility of these molecules.

Trends Neurosci. (1998) 21, 438–444

Section snippets

Insights into neurotrophic factor function from structural analyses

A three-dimensional structure, as determined by X-ray crystallographic or nuclear magnetic resonance (NMR) methods, provides information on the structural environment of each residue in the protein, whether buried or surface accessible, hydrogen bonded or making van der Waal contacts, and identifies which residues are spatially close together. Such information can be helpful in predicting the location of functional sites on the protein surface, features that may guide subsequent mutagenesis

Importance of electrostatic forces for the interaction of neurotrophic factors with their receptors

Examination of the surface properties of a molecule can help to identify functionally important regions that may provide binding surfaces to interaction with receptors. These might be flexible loops, crevices, hydrophobic patches and charged clusters. The latter contribute electrostatic forces that guide ligands to receptors to bind or collide in a productive fashion. Electrostatic interactions are generally long range and are predicted to affect the association rate of binding. Use of long

Site-directed mutagenesis and structure–activity relationships

Although analysis of the surface properties of a ligand gives information regarding the possible sites of interaction with receptors, the functional importance of individual residues needs to be assessed directly by site-directed mutagenesis. Moreover, predictions based on three-dimensional structures of ligand–receptor complexes (not yet available for neurotrophic factors) need to be confirmed by direct functional studies. Alanine-scanning mutagenesis, the systematic replacement of amino acid

Ligands with altered receptor binding specificity offer new insights into neurotrophic factor function

Taking advantage of its TrkA-only binding profile, a NGF mutant deficient in the ability to bind to p75^NTR with alanine replacements at positions 32, 34 and 35 (termed triNGF) has been used to probe for possible roles of p75^NTR in the survival responses of primary embryonic neurons to NGF (Ref. [62]). The mutant was found to be less potent than wild-type NGF at low ligand concentrations (similar to or lower than the high affinity dissociation binding constant). The reduced responsiveness to the

Concluding remarks

Understanding of structure–function relationships in families of neurotrophic factors and their receptors has not only furthered our knowledge of important aspects of the biology of these proteins, but it has also provided molecules with novel activity profiles, thereby expanding the repertoire of tools with which to explore the therapeutic applications of neurotrophic factors.

Acknowledgements

I would like to thank Judith Murray-Rust and Neil McDonald for sharing ideas and for help with the generation of figures, Alun Davies for sharing the sequence of GFRα-4 prior to publication, and members of the CIBLab and the Molecular Neurobiology Laboratory for encouragement and fruitful discussions. C.F.I. is supported by grants from the Swedish Medical Research Council, the Swedish Cancer Society and the European Commission.

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Trends in Neurosciences

Emerging themes in structural biology of neurotrophic factors

Abstract

Section snippets

Insights into neurotrophic factor function from structural analyses

Importance of electrostatic forces for the interaction of neurotrophic factors with their receptors

Site-directed mutagenesis and structure–activity relationships

Ligands with altered receptor binding specificity offer new insights into neurotrophic factor function

Concluding remarks

Acknowledgements

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