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Structure of mouse 7S NGF: a complex of nerve growth factor with four binding proteins.

Bax B, Blundell TL, Murray-Rust J, McDonald NQ
Structure 5 1275-85 (1997)
Cited: 33 times
EuropePMC logo PMID: 9351801

Abstract

Background

Nerve growth factor (NGF) is a neurotrophic factor that promotes the differentiation and survival of certain populations of neurons in the central and peripheral nervous systems. 7S NGF is an alpha 2 beta 2 gamma 2 complex in which the beta-NGF dimer (the active neurotrophin) is associated with two alpha-NGF and two gamma-NGF subunits, which belong to the glandular kallikrein family of serine proteinases. The gamma-NGF subunit is an active serine proteinase capable of processing the precursor form of beta-NGF, whereas alpha-NGF is an inactive serine proteinase. The structure of 7S NGF could be used as a starting point to design inhibitors that prevent NGF binding to its receptors, as a potential treatment of neurodegenerative diseases.

Results

The crystal structure of 7S NGF shows that the two gamma-NGF subunits make extensive interactions with each other around the twofold axis of the complex and have the C-terminal residues of the beta-NGF subunits bound within their active sites. The 'activation domain' of each of the alpha-NGF subunits is in an inactive (zymogen-like) conformation and makes extensive interactions with the beta-NGF dimer. The two zinc ions that stabilize the complex are located at the relatively small interfaces between the alpha-NGF and gamma-NGF subunits.

Conclusion

The structure of 7S NGF shows how the twofold axis of the central beta-NGF dimer organizes the symmetry of this multisubunit growth factor complex. The extensive surface of beta-NGF buried within the 7S complex explains the lack of neurotrophic activity observed for 7S NGF. The regions of the beta-NGF dimer that contact the alpha-NGF subunits overlap with those known to engage NGF receptors. Two disulphide-linked loops on alpha-NGF make multiple interactions with beta-NGF and suggest that it might be possible to design peptides that inhibit the binding of beta-NGF to its receptors.

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  3. The structure of human prokallikrein 6 reveals a novel activation mechanism for the kallikrein family. Gomis-Rüth FX, Bayés A, Sotiropoulou G, Pampalakis G, Tsetsenis T, Villegas V, Avilés FX, Coll M. J Biol Chem 277 27273-27281 (2002)
  4. 1.70 A X-ray structure of human apo kallikrein 1: structural changes upon peptide inhibitor/substrate binding. Laxmikanthan G, Blaber SI, Bernett MJ, Scarisbrick IA, Juliano MA, Blaber M. Proteins 58 802-814 (2005)
  5. Crystal structures of prethrombin-2 reveal alternative conformations under identical solution conditions and the mechanism of zymogen activation. Pozzi N, Chen Z, Zapata F, Pelc LA, Barranco-Medina S, Di Cera E. Biochemistry 50 10195-10202 (2011)
  6. Biophysical characterization of refolded Drosophila Spätzle, a cystine knot protein, reveals distinct properties of three isoforms. Hoffmann A, Funkner A, Neumann P, Juhnke S, Walther M, Schierhorn A, Weininger U, Balbach J, Reuter G, Stubbs MT. J Biol Chem 283 32598-32609 (2008)
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  14. Optimization of recombinant β-NGF expression in Escherichia coli using response surface methodology. Gholami Tilko P, Hajihassan Z, Moghimi H. Prep Biochem Biotechnol 47 406-413 (2017)
  15. AAV2/9-mediated gene transfer into murine lacrimal gland leads to a long-term targeted tear film modification. Gautier B, Meneux L, Feret N, Audrain C, Hudecek L, Kuony A, Bourdon A, Le Guiner C, Blouin V, Delettre C, Michon F. Mol Ther Methods Clin Dev 27 1-16 (2022)


Related citations provided by authors (1)

  1. Crystallization and Characterization of the High Molecular Weight Form of Nerve Growth Factor (7 S Ngf). Mcdonald NQ, Blundell TL J. Mol. Biol. 219 595- (1991)

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