Structural Determinants of the Dopamine Transporter Regulation Mediated by G Proteins
| Autor: | Roberto Rosales-Rojas, Genoveva Rojas, Jeffrey Comer, Ivana Orellana, Jennie Garcia-Olivares, Ariela Vergara-Jaque |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Neurotransmitter transporter
Dopamine Plasma Membrane Transport Proteins biology G protein Chemistry Dopamine General Chemical Engineering Protein subunit Transporter General Chemistry Molecular Dynamics Simulation Library and Information Sciences Computer Science Applications Cell biology Reuptake Drosophila melanogaster GTP-Binding Proteins Heterotrimeric G protein biology.protein Animals Drosophila Proteins Sequence motif Dopamine transporter |
| Zdroj: | Journal of Chemical Information and Modeling. 60:3577-3586 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.0c00236 |
| Popis: | Dopamine clearance in the brain is controlled by the dopamine transporter (DAT), a protein residing in the plasma membrane, which drives reuptake of extracellular dopamine into presynaptic neurons. Studies have revealed that the βγ subunits of heterotrimeric G proteins modulate DAT function through a physical association with the C-terminal region of the transporter. Regulation of neurotransmitter transporters by Gβγ subunits is unprecedented in the literature; therefore, it is interesting to investigate the structural details of this particular protein-protein interaction. Here, we refined the crystal structure of the Drosophila melanogaster DAT (dDAT), modeling de novo the N- and C-terminal domains; subsequently, we used the full-length dDAT structure to generate a comparative model of human DAT (hDAT). Both proteins were assembled with Gβ1γ2 subunits employing protein-protein docking, and subsequent molecular dynamics simulations were run to identify the specific interactions governing the formation of the hDAT:Gβγ and dDAT:Gβγ complexes. A [L/F]R[Q/E]R sequence motif containing the residues R588 in hDAT and R587 in dDAT was found as key to bind the Gβγ subunits through electrostatic interactions with a cluster of negatively charged residues located at the top face of the Gβ subunit. Alterations of DAT function have been associated with multiple devastating neuropathological conditions; therefore, this work represents a step toward better understanding DAT regulation by signaling proteins, allowing us to predict therapeutic target regions. |
| Databáze: | OpenAIRE |
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