|
The development and sustenance of specific neuronal populations in the
peripheral and central nervous systems are controlled through the binding of
neurotrophic factors to high-affinity cell surface receptors. The neurotrophins
(nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF; neurotrophin
3, NT3; and neurotrophin 4, NT4) are dimeric molecules which share approximately
50% sequence identity. The crystal structure of the murine NGF homodimer
[McDonald et al. (1991) Nature 354, 411-414] indicated that the dimer interface
corresponds to regions of high sequence conservation throughout the neurotrophin
family. This potential compatibility was duly exploited for the production in
vitro of noncovalent heterodimers between the different neurotrophins
[Radziejewski, C., & Robinson, R.C. (1993) Biochemistry 32, 13350-13356;
Jungbluth et al. (1994) Eur. J. Biochem. 221, 677-685]. Here, we report the
X-ray structure at 2.3 A resolution of one such heterodimer, between human BDNF,
and human NT3. The NGF, BDNF, and NT3 protomers share the same topology and are
structurally equivalent in regions which contribute to the dimer interface in
line with the propensity of the neurotrophins to form heterodimers. Analysis of
the structure of regions of the BDNF/NT3 heterodimer involved in receptor
specificity led us to conclude that heterodimer binding to p75 involves distant
binding sites separately located on each protomer of the heterodimer. In
contrast, heterodimer interactions with the trk receptors probably utilize
hybrid binding sites comprised of residues contributed by both protomers in the
heterodimer. The existence of such hybrid binding sites for the trk receptor
provides an explanation for the lower activity of the BDNF/NT3 heterodimer in
comparison to the homodimers.(ABSTRACT TRUNCATED AT 250 WORDS)
|
