ArticleThe Journal of biological chemistry2015
A salt bridge linking the first intracellular loop with the C terminus facilitates the folding of the serotonin transporter.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 48 citations in OpenAlex.
- Pharmacological Evaluation of Tropane Analogues at the Serotonin Transporter.ACS chemical neuroscience · 2025Article
- Rescue of Epilepsy-Associated Mutations of the Highly Conserved Glycine Residue 443 in the Human GABA Transporter 1.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- A transporter's doom or destiny:Frontiers in molecular neuroscience · 2024Review
- The cell cycle protein MAD2 facilitates endocytosis of the serotonin transporter in the neuronal soma.EMBO reports · 2023Article
- Article
- Article
- Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders.Frontiers in molecular biosciences · 2022Review
- Article
- The First Cytoplasmic Loop in the Core Structure of the ABCC1 (Multidrug Resistance Protein 1; MRP1) Transporter Contains Multiple Amino Acids Essential for Its Expression.International journal of molecular sciences · 2021Article
- Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.Pharmacology & therapeutics · 2021Review
- SLC6 transporter oligomerization.Journal of neurochemistry · 2021Review
- Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters.ACS pharmacology & translational science · 2021Article
- Article
- The Creatine Transporter Unfolded: A Knotty Premise in the Cerebral Creatine Deficiency Syndrome.Frontiers in synaptic neuroscience · 2020Review
- Human Serotonin Transporter Coding Variation Establishes Conformational Bias with Functional Consequences.ACS chemical neuroscience · 2019Article
- Functional and structural analysis of rare SLC2A2 variants associated with Fanconi-Bickel syndrome and metabolic traits.Human mutation · 2019Article
- How to rescue misfolded SERT, DAT and NET: targeting conformational intermediates with atypical inhibitors and partial releasers.Biochemical Society transactions · 2019Review
- Tales of tails in transporters.Open biology · 2019Review
- Insights into the mechanism and pharmacology of neurotransmitter sodium symporters.Current opinion in structural biology · 2019Review
- Structural basis for recognition of diverse antidepressants by the human serotonin transporter.Nature structural & molecular biology · 2018Article
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Authors and funding
8 authors at 1 institution in 2 countries.
Funding
Abstract
The folding trajectory of solute carrier 6 (SLC6) family members is of interest because point mutations result in misfolding and thus cause clinically relevant phenotypes in people. Here we examined the contribution of the C terminus in supporting folding of the serotonin transporter (SERT; SLC6A4). Our working hypothesis posited that the amphipathic nature of the C-terminal α-helix (Thr(603)-Thr(613)) was important for folding of SERT. Accordingly, we disrupted the hydrophobic moment of the α-helix by replacing Phe(604), Ile(608), or Ile(612) by Gln. The bulk of the resulting mutants SERT-F604Q, SERT-I608Q, and SERT-I612Q were retained in the endoplasmic reticulum, but their residual delivery to the cell surface still depended on SEC24C. This indicates that the amphipathic nature of the C-terminal α-helix was dispensable to endoplasmic reticulum export. The folding trajectory of SERT is thought to proceed through the inward facing conformation. Consistent with this conjecture, cell surface expression of the misfolded mutants was restored by (i) introducing second site suppressor mutations, which trap SERT in the inward facing state, or (ii) by the pharmacochaperone noribogaine, which binds to the inward facing conformation. Finally, mutation of Glu(615) at the end of the C-terminal α-helix to Lys reduced surface expression of SERT-E615K. A charge reversal mutation in intracellular loop 1 restored surface expression of SERT-R152E/E615K to wild type levels. These observations support a mechanistic model where the C-terminal amphipathic helix is stabilized by an intramolecular salt bridge between residues Glu(615) and Arg(152). This interaction acts as a pivot in the conformational search associated with folding of SERT.
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