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

International Journal of Molecular Sciences
Koichi UegakiMasami Kojima

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 wi...Continue Reading

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Citations

Feb 26, 2019·Genes, Brain, and Behavior·Li-Ching LeeChun-Yen Chang
Apr 19, 2019·PloS One·Clara Carolina Silva De OliveiraJoelma Freire De Mesquita
Sep 9, 2020·Cell and Tissue Research·Masami KojimaTeiichi Furuichi
Jun 6, 2018·Frontiers in Molecular Neuroscience·Shih-Jen Tsai
May 12, 2019·Cell and Tissue Research·Masami KojimaToshiyuki Mizui
Jun 25, 2019·Frontiers in Psychology·Raíssa Nóbrega de AlmeidaNicole Leite Galvão-Coelho
Jan 29, 2019·Frontiers in Cellular Neuroscience·Claire Emma McGregor, Arthur W English
Dec 29, 2020·Progress in Neuro-psychopharmacology & Biological Psychiatry·Thibaut GelleMurielle Girard
Aug 20, 2019·Frontiers in Neuroendocrinology·Gilmara Gomes de Assis, Eugene V Gasanov
Oct 15, 2020·International Journal of Molecular Sciences·Frank J RaucciCristi L Galindo
May 25, 2021·Frontiers in Molecular Neuroscience·Gilmara Gomes de AssisEugene V Gasanov
Sep 9, 2021·Biochemical Society Transactions·Matthew RatcliffMarko Hyvönen

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Methods Mentioned

BETA
surface plasmon resonance
chip
X-ray

Software Mentioned

BIAevaluation
ZDOCK

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