28 November 2024
Scientists from the Institute of Molecular and Cellular Physiology (IBI-1) and the Institute of Computational Biomedicine (INM-9) of the Forschungszentrum Jülich have now studied the molecular functioning of a bacterial model protein of vesicular glutamate transporters at unprecedented accuracy. The findings provide a better understanding of transport processes that are crucial for communication between neurons. The results have been published in the renowned EMBO Journal.
Chemical synapses are responsible for many of the unique features of our brain. They support communication between neurons using specialized signaling molecules called neurotransmitters. Neurons release neurotransmitters, which then bind and trigger new signals in the postsynaptic neuron, i.e. the neuron that receives the signal. Neurotransmitters are released by the fusion of little bubbles called vesicles to the cell membrane. Synaptic transmission requires the selective and effective filling of these vesicles by specialized neurotransmitter transporters.
From bacteria to humans: model proteins as research tools
Many human transport proteins have evolutionary origins that extend back to the world of bacteria. These bacterial model proteins often have a similar structure as their human counterparts, but a less complex function, making them easier to study. The Jülich scientists studied a D-galactonate transporter (DgoT) from E. coli. This protein is closely related to the human vesicular glutamate transporter, which accumulates the neurotransmitters glutamate into synaptic vesicles. Using a combination of experiments with atomistic and quantum mechanical molecular dynamics simulations, the researchers provided an accurate functional description across multiple time scales (Fig. 1).
Transport mechanisms in atomic detail
DgoT uses proton gradients as an energy source for galactonate transport against its concentration gradient and thus against the natural flow of molecules (see video below). Transport is initiated by protonation –attachment of protons – to two key amino acids. This opens an external gate and allows D-galactonate to bind. A subsequent major change in shape closes the transporter to the outside and opens it to the inside. Release of the first of the two protons triggers the dissociation of galactonate to the inside. After deprotonation of the other amino acid, the empty transporter then returns to its original form.
The new results describe the transport mechanism of DgoT at atomic resolution and provide a starting point for similar studies on vesicular glutamate transporters.
Social and scientific relevance
The comprehensive understanding of our brain requires the description of cellular functions at the level of individual molecules/atoms. Such analyses provide an accurate view on cellular and supra-cellular functions, and may help development of novel therapeutic concepts that modify the function of defined proteins. Diseases that are caused by altered protein functions, these results may be treated by restoring the function of the pathologically altered proteins.
Original publication in the EMBO journal
Dmitrieva, N., Gholami, S., Alleva, C., Carloni, P., Alfonso-Prieto, M., & Fahlke, C. (2024). Transport mechanism of DgoT, a bacterial homolog of SLC17 organic anion transporters. The EMBO Journal. https://doi.org/10.1038/s44318-024-00279-y
