The SLC17 family of transporters plays crucial roles in the body. Some members, such as VGLUTs, help accumulate neurotransmitters in secretory vesicles. Others, like Sialin, remove carboxylated monosaccharides from lysosomes, while some assist the kidneys and liver in eliminating organic anions. Despite decades of research, the mechanisms underlying SLC17 organic anion transport remain poorly understood.

To gain insights into the complex and diverse transport mechanisms of SLC17 transporters, a recent study examined DgoT, a bacterial transporter homologous to mammalian SLC17 members. DgoT transports negatively charged galactonate in symport with multiple protons, making it a valuable model for studying SLC17 transport mechanisms.

Using molecular dynamics simulations, quantum mechanics/molecular mechanics (QM/MM) simulations, mutational analysis, and solid-supported membrane electrophysiology (SSME), the study provides an in-depth view of DgoT’s transport cycle:

1. The process begins with protonation of two key amino acids, D46 and E133, before galactonate binds.
2. Upon galactonate binding, the extracellular gate of the protein closes.
3. The protein undergoes a conformational change, shifting from an outward-facing to an inward-facing state.
4. Next, E133 loses its proton, and D46 transfers its proton to E133, causing the intracellular gate to open.
5. Galactonate is then released into the cell, either in its original form or after protonation.
6. Finally, the protein releases its remaining proton and resets to its original outward-facing conformation.

Four charged amino acids – D46, R47, R126, and E133 – were identified as crucial for DgoT’s function. Notably, the last three are conserved across the SLC17 family, underscoring their importance within this family of transporters.

In conclusion, this study of DgoT provides a model for understanding other proton-coupled SLC17 transporters, showing how subtle structural and functional changes enable diverse transport functions across the family.

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Find the full article here: Transport mechanism of DgoT, a bacterial homolog of SLC17 organic anion transporters

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