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C-terminal mutation induces a folding defect in the serotonin transporter

Neurotransmitter transporters are responsible for terminating signal transmission. hSERT (the human serotonin transporter) is the plasma membrane Na+/Cl--dependent transporter which is responsible for uptake of serotonin from the synaptic cleft. A previous study has shown that deleting the C-terminus of SERT impaired transporter activity and compromised its delivery to the plasma membrane) [1]. However, this study did not provide a mechanistic explanation. Alanine-scanning mutagenesis strategy was used in order to delineate which part of the C-terminus of SERT was required for folding of the protein. Pairs of alanine substitutions by site-directed mutagenesis have been produced and we are currently in the process of testing the effect of these mutations on the functional properties and the cellular localization of SERT. The preliminary data show that the mutation in P601G602-AA and R607I608-AA (Sec24 binding site) causes intracellular retention and abolishes uptake and binding.

References

  1. Larsen MB, Fjorback AW, Wiborg O: The C-terminus is critical for the functional expression of the human serotonin transporter. Biochemistry. 2006, 45: 1331-1337. 10.1021/bi0508688.

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Acknowledgements

This work is supported by: SFB35-10 and stipend from Egyptian Ministry of Higher Education and State for Scientific Research.

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Correspondence to Subhodeep Sarker.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Elkasaby, A., Sarker, S. & Just, H. C-terminal mutation induces a folding defect in the serotonin transporter. BMC Pharmacol 8 (Suppl 1), A7 (2008). https://doi.org/10.1186/1471-2210-8-S1-A7

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  • DOI: https://doi.org/10.1186/1471-2210-8-S1-A7

Keywords

  • Serotonin
  • Alanine
  • Transporter Activity
  • Signal Transmission
  • Cellular Localization