Abstract
BackgroundNeurotrophins and their receptors play crucial roles in the development and functioning of nervous systems. It is widely believed that neurotrophin‐induced dimerization of the receptors initiates the transmembrane signalling. However, it is still controversial whether the receptor molecules have a monomeric or dimeric structure on the cell surface before its ligand binding.FindingsUsing chemical cross‐linking, bimolecular fluorescence complementation assay and luciferase fragment complementation assay, in this study, we show the brain‐derived neurotrophic factor (BDNF) receptor TrkB exists as a homo‐dimer before ligand binding. We also report that the receptor fs intracellular domain is critical for the formation of the dimeric structure, since mutant receptors lacking its intracellular domain failed to have the homodimeric structure, and that the dimer is formed in the endoplasmic reticulum before the newly synthesized receptors reach the cell surface.ConclusionsMost, if not all, of the TrkB receptor has a preformed, yet inactive, homodimeric structure before BDNF binding. The intracellular domain of TrkB plays a crucial role in the spontaneous dimerization of the newly synthesized receptors, which occurs in ER. These findings provide new insight into an understanding of a molecular mechanism underlying transmembrane signaling mediated by neurotrophin receptors.
Highlights
Neurotrophins (NTs) and their receptors play crucial roles in the development, functions and maintenance of nervous systems
The intracellular domain of TrkB plays a crucial role in the spontaneous dimerization of the newly synthesized receptors, which occurs in endoplasmic reticulum (ER)
These findings provide new insight into an understanding of a molecular mechanism underlying transmembrane signaling mediated by NT receptors
Summary
If not all, of the TrkB receptor has a preformed, yet inactive, homodimeric structure before BDNF binding. The band intensity of the TrkB dimer cross-linked was similar in the absence and presence of BDNF (Figure 1C) These results suggest either that a fraction of TrkB exists as a preformed dimer, or that only a fraction of the receptor dimers was expressed on the cell surface and was chemically crosslinked. Together with the results shown, these results confirm that the BiFC fusion receptors behave like the wild-type receptor, and suggest again that TrkB exists as an inactive dimer, which can be activated by BDNF binding. The fluorescence inside the cells was mainly co-localized with calnexin, an ER marker [15] These results indicate that TrkB spontaneously dimerizes in ER before the newly synthesized receptor reaches the cell surface. No Venus fluorescence was observed in HEK 293 cells co-expressing TrkBΔICD-VN and TrkBΔICD-VC, both
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