K. Kullander et al., 2 RESTRICTED SITES ON THE SURFACE OF THE NERVE GROWTH-FACTOR MOLECULEINDEPENDENTLY DETERMINE SPECIFIC TRKA RECEPTOR-BINDING AND ACTIVATION, The Journal of biological chemistry, 272(14), 1997, pp. 9300-9307
Nerve growth factor (NGF) and neurotrophin-3 (NT-3) mediate activities
such as survival, differentiation, and proliferation in various subse
ts of neurons, In this report, we define precisely the residues in hum
an NGF responsible for NGF biological activity and binding specificity
to the neurotrophin receptor TrkA. In earlier studies we defined five
amino acid residues of NGF which confer NGF-like activity to NT-3 whe
n replacing corresponding residues in the 120-amino acid long NT-3 mol
ecule. Using this gain-of-function strategy we report the further diss
ection of this functional epitope. We also define another motif separa
ted topographically in the NGF dimer and determined to be independentl
y responsible for NGF specificity. The first of the two motifs determi
ned to elicit NGF specificity is defined by the residues Val-48, Pro-4
9, and Gln-96, which are situated in the two top beta-loops of NGF. Th
e second motif is represented by residues Pro-5 and Phe-7 situated in
the proximal part of the NH2 terminus. Both motifs contain structurall
y important residues revealing a novel principle, where specificity fo
r neurotrophin ligand-receptor interactions could be determined by var
iable residues modifying the conformation of the neurotrophin backbone
. These findings will enhance further the possibility of mimicking NGF
with low molecular weight compounds.