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

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.

Impact of brain‐derived neurotrophic factor genetic polymorphism on cognition: A systematic review

“…This polymorphism change has been linked to aberrant sorting of pro‐BDNF into secretory vesicles and decreased activity‐dependent secretion of BDNF which constitutes the main process in the regulation of extracellular levels of BDNF (Wei et al., ). There has also been suggestion by a study that this polymorphism may influence the interaction between mature and pro‐BDNF, affecting the stability of the complex formed between the two and attenuating the ability of BDNF to inhibit hippocampal long‐term depression (Uegaki et al., ).…”

Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment

“…In addition, several proteins are described to influence BDNF trafficking, examples include, but are not limited to: α-synuclein (Fang et al, 2017), huntingtin (Ma et al, 2010), translin (Wu et al, 2011), and the heterogeneous nuclear ribonucleoprotein CArG Box binding Factor A (Raju et al, 2011). A recent study has depicted that mBDNF capacity of compromising hippocampal LTD is impaired inasmuch as BDNF-propeptide is able to bind to mBDNF with a higher affinity (Uegaki et al, 2017). Complementary, TrkB gene can be translated into four versions, the full-length TrkB and the truncated versions originated from splice variants (Sasi et al, 2017).…”

The BDNF rs6265 Polymorphism is a Modifier of Cardiomyocyte Contractility and Dilated Cardiomyopathy

“…In approximately 30% of the general population, the prodomain of BDNF has a nonsynonymous (G→A) single nucleotide polymorphism (SNP) at codon position 66 (rs6265), resulting in replacement of valine (Val) with methionine (Met) [ 5 ]. The Val66→Met substitution substantially increases the binding stability of the prodomain to mature BDNF, consequently reducing BDNF’s trafficking and secretion [ 6 , 7 ]. Val→Met may additionally alter receptor binding and signaling of proBDNF [ 8 ], as well as confer biological activity on the secreted prodomain itself [ 4 ].…”