Database accession: MF2200009
Name: Brain-derived neurotrophic factor/neurotrophin 3 heterodimer
PDB ID: 1bnd
Experimental method: X-ray (2.30 Å)
Assembly: heterodimer
Source organism: Homo sapiens
Primer publication of the structure:
Robinson RC, Radziejewski C, Stuart DI, Jones EY
Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer.
(1995) Biochemistry 34: 4139-46
PMID: 7703225
Abstract:
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)
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
growth factor activity The function that stimulates a cell to grow or proliferate. Most growth factors have other actions besides the induction of cell growth or proliferation.
Biological process:
negative regulation of neuron apoptotic process Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process in neurons.
nervous system development The process whose specific outcome is the progression of nervous tissue over time, from its formation to its mature state.
Cellular component:
cytoplasmic, membrane-bounded vesicle A membrane-bounded vesicle found in the cytoplasm of the cell.
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, B
Notes: No modifications of the original PDB file. Chain identifiers are identical with the PDB's identifiers.
Number of unique protein segments: 2
Name: Brain-derived neurotrophic factor
Source organism: Homo sapiens
Length: 119 residues
Sequence:Sequence according to PDB SEQRESHSDPARRGQLSVCDSISEWVTAADKKTAVDMSGGTVTVLEKVPVSKGQLKQYFYETKCNPMGYTKEGCRGIDKRHWNSQCRTTQSYVRALTMDSKKRIGWRFIRIDTSCVCTLTIKRGR
UniProtKB AC: P23560 (positions: 129-247) Coverage: 48.2%
UniRef90 AC: UniRef90_P23560 (positions: 129-247)
Name: Neurotrophin-3
Source organism: Homo sapiens
Length: 119 residues
Sequence:Sequence according to PDB SEQRESYAEHKSHRGEVSVCDSESLWVTDKSSAIDIRGHQVTVLGEIKTQNSPVKQYFYETRCKEARPVKNGCRGIDDKHWNSQCKTSQTYVRALTSENNKLVGWRWIRIDTSCVCALSRKIGRT
UniProtKB AC: P20783 (positions: 139-257) Coverage: 46.3%
UniRef90 AC: UniRef90_P20783 (positions: 139-257)
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Complex evidence:
Various dimeric members of neurotrophic factors (including human/mouse nerve growth factor, human brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5)) have been shown to fold and dimerize at the same time via a two-state process (PMID: 8161524). While the members of this family show a significant variance in sequence, they adopt a highly similar structure upon binding and behave almost identically in unfolding/refolding experiments. Thus the two-state folding/binding nature seems to be a hallmark of NGF and closely related proteins.
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). No related structure was found in the Protein Data Bank.
