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  3. BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction

  • Int J Mol Sci. 2017 May 12;18(5):1042. doi: 10.3390/ijms18051042.
Koichi Uegaki 1 2,  Haruko Kumanogoh 3 4,  Toshiyuki Mizui 5 6,  Takatsugu Hirokawa 7 8 9,  Yasuyuki Ishikawa 10 11,  Masami Kojima 12 13 14
Affiliations

Affiliations

  • 1 Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan. k-uegaki@aist.go.jp.
  • 2 Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan. k-uegaki@aist.go.jp.
  • 3 Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan. h.kumanogoh@gmail.com.
  • 4 Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan. h.kumanogoh@gmail.com.
  • 5 Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan. t-mizui@aist.go.jp.
  • 6 Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan. t-mizui@aist.go.jp.
  • 7 Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan. t-hirokawa@aist.go.jp.
  • 8 Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan. t-hirokawa@aist.go.jp.
  • 9 Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan. t-hirokawa@aist.go.jp.
  • 10 Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan. yishikaw@maebashi-it.ac.jp.
  • 11 Department of Systems Life Engineering, Maebashi Institute of Technology 460-1, Kamisadori, Maebashi 370-0816, Japan. yishikaw@maebashi-it.ac.jp.
  • 12 Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan. m-kojima@aist.go.jp.
  • 13 Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan. m-kojima@aist.go.jp.
  • 14 Graduate School of Frontier Bioscience, Osaka University, Suita 565-0871, Japan. m-kojima@aist.go.jp.
PMID: 28498321 DOI: 10.3390/ijms18051042
Abstract

Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function and assists the folding of the BDNF protein. However, our results suggest a new role for the BDNF pro-domain (or pro-peptide) following proteolytic cleave of precursor BDNF, and provide insight into the Val66Met polymorphism.

Keywords

BDNF; hippocampus; long-term depression; polymorphism; pro-peptide.

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