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PreprintCited by 17Protein Structure and DynamicsReceptor Mechanisms and SignalingDrug Transport and Resistance Mechanisms

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Structural rearrangement of the intracellular gate of the serotonin transporter induced by Thr276 phosphorylation

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Chan, Matthew C., Procko, Erik, Shukla, Diwakar·2021·ACS Chemical Neuroscience
DOI 10.1101/2021.10.13.464332

Preprint — published as 10.1021/acschemneuro.1c00714 · Paper page

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Abstract

The reuptake of the neurotransmitter serotonin from the synaptic cleft by the serotonin transporter, SERT, is essential for proper neurological signaling. Biochemical studies have shown Thr276 of transmembrane helix 5 is a site of PKG-mediated SERT phosphorylation, which has been proposed to shifts the SERT conformational equlibira to promote inward-facing states, thus enhancing 5HT transport. Recent structural and simulation studies have provided insights into the conformation transitions during substrate transport but have not shed light on SERT regulation via post-translational modifications. Using molecular dynamics simulations and Markov state models, we investigate how Thr276 phosphorylation impacts the SERT mechanism and its role in enhancing transporter stability and function. Our simulations show that Thr276 phosphorylation alters the hydrogen-bonding network involving residues on transmembrane helix 5. This in turn decreases the free energy barriers for SERT to transition to the inward-facing state, thus facilitating 5HT transport. The results provide atomistic insights into in vivo SERT regulation and can be extended to other pharmacologically important transporters in the solute carrier superfamily.

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Metadata

Authors
Chan, M. C., Procko, E., & Shukla, D.
Affiliations
University of Illinois Urbana-Champaign (US)
Corresponding author
Shukla, Diwakar
ORCID
Venue
ACS Chemical Neuroscience
Publisher
openRxiv
Published
2021-10-15
Volume
13
Issue
7
Pages
933-945
ISSN
1948-7193 (ISSN-L)
DOI
10.1101/2021.10.13.464332
OpenAlex
W4220730207
Cited by
17
References
1
Citations by year
2025: 3 · 2024: 6 · 2023: 3 · 2022: 5
FWCI
1.39
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • ACS Chemical Neuroscience (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (0725070, 1845606, 45606, (OCI 07‐25070), 1238993)
  • National Geospatial-Intelligence Agency
  • University of Illinois at Urbana-Champaign (OCI-0725070, ACI-1238993)
  • National Institute of Mental Health (R21MH113155)
  • Division of Molecular and Cellular Biosciences (MCB1845606)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
serotonin transporter, transmembrane helix 5, intracellular gate, serotonin uptake, hydrogen bond network, activation barrier, post-translational modification, solute carrier transporters, Markov state models
MeSH terms
Biological Transport, Phosphorylation, Serotonin, Serotonin Plasma Membrane Transport Proteins, Molecular Dynamics Simulation

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