Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors.
Neurotrophin-3 (NT-3) is a cystine knot growth factor that promotes the survival, proliferation, and differentiation of developing neurons and is a potential therapeutic for neurodegenerative diseases. To clarify the structural basis of receptor specificity and the role of neurotrophin dimerization in receptor activation, the structure of the NT-3 homodimer was determined using X-ray crystallography. The orthorhombic crystals diffract to 2.4 A, with dimer symmetry occurring about a crystallographic 2-fold axis. The overall structure of NT-3 resembles that of the other neurotrophins, NGF and BDNF; each protomer forms a twisted four-stranded beta sheet, with three intertwined disulfide bonds. There are notable differences, however, between NT-3 and NGF in the surface loops and in three functionally important regions, shown in previous mutagenesis studies to be critical for binding. One such difference implies that NT-3's binding affinity and specificity depend on a novel hydrogen bond between Gln 83, a residue important for binding specificity with TrkC, and Arg 103, a residue crucial for binding affinity with TrkC. NT-3's extensive dimer interface buries much of the otherwise solvent-accessible hydrophobic surface area and suggests that the dimeric state is stabilized through the formation of this hydrophobic core. A comparison of the dimer interface between the NT-3 homodimer and the BDNF/NT-3 heterodimer reveals similar patterns of hydrogen bonds and nonpolar contacts, which reinforces the notion that the evolutionarily conserved neurotrophin interface resulted from the need for receptor dimerization in signal initiation.
Butte
M J
MJ
Graduate Group in Biophysics and Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA.
Hwang
P K
PK
Mobley
W C
WC
Fletterick
R J
RJ
D000595:Amino Acid Sequence; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000737:chemistry* / Q000378:metabolism; D020933:Neurotrophin 3; D011487:Protein Conformation; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor