How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties

Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel

doi:10.1186/s12915-018-0495-6

Title: How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties

Journal Article · Wed Mar 14 00:00:00 EDT 2018 · BMC Biology

DOI:https://doi.org/10.1186/s12915-018-0495-6· OSTI ID:1626874

Razavi, Asghar M. ^[1]; Khelashvili, George ^[2];

^[2]

Cornell Univ., Ithaca, NY (United States)
Cornell Univ., Ithaca, NY (United States). Weill Cornell Medical College, Inst. for Computational Biomedicine

Background. Much of the structure-based mechanistic understandings of the function of SLC6A neurotransmitter transporters emerged from the study of their bacterial LeuT-fold homologs. It has become evident, however, that structural differences such as the long N- and C-termini of the eukaryotic neurotransmitter transporters are involved in an expanded set of functional properties to the eukaryotic transporters. These functional properties are not shared by the bacterial homologs, which lack the structural elements that appeared later in evolution. However, mechanistic insights into some of the measured functional properties of the eukaryotic transporters that have been suggested to involve these structural elements are sparse or merely descriptive. Results. To learn how the structural elements added in evolution enable mechanisms of the eukaryotic transporters in ways not shared with their bacterial LeuT-like homologs, we focused on the human dopamine transporter (hDAT) as a prototype. We present the results of a study employing large-scale molecular dynamics simulations and comparative Markov state model analysis of experimentally determined properties of the wild-type and mutant hDAT constructs. These offer a quantitative outline of mechanisms in which a rich spectrum of interactions of the hDAT N-terminus and C-terminus contribute to the regulation of transporter function (e.g., by phosphorylation) and/or to entirely new phenotypes (e.g., reverse uptake (efflux)) that were added in evolution. Conclusions. The findings are consistent with the proposal that the size of eukaryotic neurotransmitter transporter termini increased during evolution to enable more functions (e.g., efflux) not shared with the bacterial homologs. The mechanistic explanations for the experimental findings about the modulation of function in DAT, the serotonin transporter, and other eukaryotic transporters reveal separate roles for the distal and proximal segments of the much larger N-terminus in eukaryotic transporters compared to the bacterial ones. The involvement of the proximal and distal segments — such as the role of the proximal segment in sustaining transport in phosphatidylinositol 4,5-bisphosphate-depleted membranes and of the distal segment in modulating efflux — may represent an evolutionary adaptation required for the function of eukaryotic transporters expressed in various cell types of the same organism that differ in the lipid composition and protein complement of their membrane environment.

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Research Organization:: Cornell Univ., Ithaca, NY (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725; AC02-05CH11231; P01 DA012408; R01 DA041510

OSTI ID:: 1626874

Journal Information:: BMC Biology, Vol. 16, Issue 1; ISSN 1741-7007

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

References (88)

Monoamine neurotransmitter disorders—clinical advances and future perspectives Ng, Joanne; Papandreou, Apostolos; Heales, Simon J. Nature Reviews Neurology, Vol. 11, Issue 10 https://doi.org/10.1038/nrneurol.2015.172	journal	September 2015
Spontaneous Inward Opening of the Dopamine Transporter is Triggered by PIP2-Regulated Dynamics of the N-Terminus Khelashvili, George; Stanley, Nathaniel; Sahai, Michelle Biophysical Journal, Vol. 110, Issue 3 https://doi.org/10.1016/j.bpj.2015.11.3354	journal	February 2016
Atypical dopamine efflux caused by 3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter Shekar, Aparna; Aguilar, Jenny I.; Galli, Greta Journal of Chemical Neuroanatomy, Vol. 83-84 https://doi.org/10.1016/j.jchemneu.2017.01.004	journal	October 2017
Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter LeVine, Michael V.; Cuendet, Michel A.; Razavi, Asghar M. Biophysical Journal, Vol. 114, Issue 1 https://doi.org/10.1016/j.bpj.2017.10.030	journal	January 2018
Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux Yang, Jae-Won; Foster, James D.; Moritz, Amy E. BMC Pharmacology and Toxicology, Vol. 13, Issue S1 https://doi.org/10.1186/2050-6511-13-s1-a45	journal	September 2012
A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/srep40076	journal	January 2017
Modeling and Dynamics of the Inward-Facing State of a Na+/Cl− Dependent Neurotransmitter Transporter Homologue Shaikh, Saher Afshan; Tajkhorshid, Emad PLoS Computational Biology, Vol. 6, Issue 8 https://doi.org/10.1371/journal.pcbi.1000905	journal	August 2010
De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder Hamilton, P. J.; Campbell, N. G.; Sharma, S. Molecular Psychiatry, Vol. 18, Issue 12 https://doi.org/10.1038/mp.2013.102	journal	August 2013
Drosophila melanogaster: a novel animal model for the behavioral characterization of autism-associated mutations in the dopamine transporter gene Hamilton, P. J.; Campbell, N. G.; Sharma, S. Molecular Psychiatry, Vol. 18, Issue 12 https://doi.org/10.1038/mp.2013.157	journal	November 2013
Molecular Mechanism of Dopamine Transport by Human Dopamine Transporter Cheng, Mary Hongying; Bahar, Ivet Structure, Vol. 23, Issue 11 https://doi.org/10.1016/j.str.2015.09.001	journal	November 2015
How Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission Sulzer, David Neuron, Vol. 69, Issue 4 https://doi.org/10.1016/j.neuron.2011.02.010	journal	February 2011
MSMBuilder: Statistical Models for Biomolecular Dynamics Harrigan, Matthew P.; Sultan, Mohammad M.; Hernández, Carlos X. Biophysical Journal, Vol. 112, Issue 1 https://doi.org/10.1016/j.bpj.2016.10.042	journal	January 2017
Simple few-state models reveal hidden complexity in protein folding Beauchamp, K. A.; McGibbon, R.; Lin, Y. -S. Proceedings of the National Academy of Sciences, Vol. 109, Issue 44 https://doi.org/10.1073/pnas.1201810109	journal	July 2012
Slow Unfolded-State Structuring in Acyl-CoA Binding Protein Folding Revealed by Simulation and Experiment Voelz, Vincent A.; Jäger, Marcus; Yao, Shuhuai Journal of the American Chemical Society, Vol. 134, Issue 30 https://doi.org/10.1021/ja302528z	journal	July 2012
A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters Malinauskaite, Lina; Quick, Matthias; Reinhard, Linda Nature Structural & Molecular Biology, Vol. 21, Issue 11 https://doi.org/10.1038/nsmb.2894	journal	October 2014
PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein Hamilton, Peter J.; Belovich, Andrea N.; Khelashvili, George Nature Chemical Biology, Vol. 10, Issue 7 https://doi.org/10.1038/nchembio.1545	journal	June 2014
Direct PIP2 binding mediates stable oligomer formation of the serotonin transporter Anderluh, Andreas; Hofmaier, Tina; Klotzsch, Enrico Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms14089	journal	January 2017
The effect of acidic pH on the adsorption and lytic activity of the peptides Polybia-MP1 and its histidine-containing analog in anionic lipid membrane: a biophysical study by molecular dynamics and spectroscopy Martins, Ingrid Bernardes Santana; Viegas, Taisa Giordano; dos Santos Alvares, Dayane Amino Acids, Vol. 53, Issue 5 https://doi.org/10.1007/s00726-021-02982-0	journal	April 2021
Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP ₂ -containing membranes : Modeling of DAT N-Terminus/PIP Khelashvili, George; Doktorova, Milka; Sahai, Michelle A. Proteins: Structure, Function, and Bioinformatics, Vol. 83, Issue 5 https://doi.org/10.1002/prot.24792	journal	March 2015
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters Yamashita, Atsuko; Singh, Satinder K.; Kawate, Toshimitsu Nature, Vol. 437, Issue 7056 https://doi.org/10.1038/nature03978	journal	July 2005
Identification of slow molecular order parameters for Markov model construction Perez-Hernandez, Guillermo; Paul, Fabian; Giorgino, Toni arXiv https://doi.org/10.48550/arxiv.1302.6614	text	January 2013
Calmodulin Kinase II Interacts with the Dopamine Transporter C Terminus to Regulate Amphetamine-Induced Reverse Transport Fog, Jacob U.; Khoshbouei, Habibeh; Holy, Marion Neuron, Vol. 51, Issue 4 https://doi.org/10.1016/j.neuron.2006.06.028	journal	August 2006
Complex Pathways in Folding of Protein G Explored by Simulation and Experiment Lapidus, Lisa J.; Acharya, Srabasti; Schwantes, Christian R. Biophysical Journal, Vol. 107, Issue 4 https://doi.org/10.1016/j.bpj.2014.06.037	journal	August 2014
Anomalous Dopamine Release Associated with a Human Dopamine Transporter Coding Variant Mazei-Robison, M. S.; Bowton, E.; Holy, M. Journal of Neuroscience, Vol. 28, Issue 28 https://doi.org/10.1523/jneurosci.0473-08.2008	journal	July 2008
N-Terminal Phosphorylation of the Dopamine Transporter Is Required for Amphetamine-Induced Efflux Khoshbouei, Habibeh; Sen, Namita; Guptaroy, Bipasha PLoS Biology, Vol. 2, Issue 3 https://doi.org/10.1371/journal.pbio.0020078	journal	March 2004
MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories McGibbon, Robert T.; Beauchamp, Kyle A.; Harrigan, Matthew P. Biophysical Journal, Vol. 109, Issue 8 https://doi.org/10.1016/j.bpj.2015.08.015	journal	October 2015
SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking Bowton, E.; Saunders, C.; Reddy, I. A. Translational Psychiatry, Vol. 4, Issue 10 https://doi.org/10.1038/tp.2014.90	journal	October 2014
Markov models of molecular kinetics: Generation and validation Prinz, Jan-Hendrik; Wu, Hao; Sarich, Marco The Journal of Chemical Physics, Vol. 134, Issue 17 https://doi.org/10.1063/1.3565032	journal	May 2011
Attention Deficit/Hyperactivity Disorder-Derived Coding Variation in the Dopamine Transporter Disrupts Microdomain Targeting and Trafficking Regulation Sakrikar, D.; Mazei-Robison, M. S.; Mergy, M. A. Journal of Neuroscience, Vol. 32, Issue 16 https://doi.org/10.1523/JNEUROSCI.6033-11.2012	journal	April 2012
Markov state models of biomolecular conformational dynamics Chodera, John D.; Noé, Frank Current Opinion in Structural Biology, Vol. 25 https://doi.org/10.1016/j.sbi.2014.04.002	journal	April 2014
Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity Kapoor, Abhijeet; Martinez-Rosell, Gerard; Provasi, Davide Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-11483-8	journal	September 2017
Rare Autism-Associated Variants Implicate Syntaxin 1 (STX1 R26Q) Phosphorylation and the Dopamine Transporter (hDAT R51W) in Dopamine Neurotransmission and Behaviors Cartier, Etienne; Hamilton, Peter J.; Belovich, Andrea N. EBioMedicine, Vol. 2, Issue 2 https://doi.org/10.1016/j.ebiom.2015.01.007	journal	February 2015
Computational characterization of structural dynamics underlying function in active membrane transporters Li, Jing; Wen, Po-Chao; Moradi, Mahmoud Current Opinion in Structural Biology, Vol. 31 https://doi.org/10.1016/j.sbi.2015.04.001	journal	April 2015
Mechanisms of neurotransmitter release by amphetamines: A review Sulzer, David; Sonders, Mark S.; Poulsen, Nathan W. Progress in Neurobiology, Vol. 75, Issue 6 https://doi.org/10.1016/j.pneurobio.2005.04.003	journal	April 2005
Slow dynamics in protein fluctuations revealed by time-structure based independent component analysis: The case of domain motions Naritomi, Yusuke; Fuchigami, Sotaro The Journal of Chemical Physics, Vol. 134, Issue 6 https://doi.org/10.1063/1.3554380	journal	February 2011
Does reverse transport of dopamine play a role in autism? Emanuele, Enzo EBioMedicine, Vol. 2, Issue 2 https://doi.org/10.1016/j.ebiom.2015.01.012	journal	February 2015
Complete protein–protein association kinetics in atomic detail revealed by molecular dynamics simulations and Markov modelling Plattner, Nuria; Doerr, Stefan; De Fabritiis, Gianni Nature Chemistry, Vol. 9, Issue 10 https://doi.org/10.1038/nchem.2785	journal	June 2017
Missense dopamine transporter mutations associate with adult parkinsonism and ADHD Hansen, Freja H.; Skjørringe, Tina; Yasmeen, Saiqa Journal of Clinical Investigation, Vol. 124, Issue 7 https://doi.org/10.1172/JCI73778	journal	June 2014
Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways Kohlhoff, Kai J.; Shukla, Diwakar; Lawrenz, Morgan Nature Chemistry, Vol. 6, Issue 1 https://doi.org/10.1038/nchem.1821	journal	December 2013
The N Terminus of Monoamine Transporters Is a Lever Required for the Action of Amphetamines Sucic, Sonja; Dallinger, Stefan; Zdrazil, Barbara Journal of Biological Chemistry, Vol. 285, Issue 14 https://doi.org/10.1074/jbc.m109.083154	journal	January 2010
Membrane lipids are key modulators of the endocannabinoid-hydrolase FAAH Dainese, Enrico; De Fabritiis, Gianni; Sabatucci, Annalaura Biochemical Journal, Vol. 457, Issue 3 https://doi.org/10.1042/bj20130960	journal	January 2014
Membrane cholesterol access into a G-protein-coupled receptor Guixa-Gonzalez, Ramon; Albasanz, Jose L.; Rodriguez-Espigares, Ismael Charité - Universitätsmedizin Berlin https://doi.org/10.17169/refubium-24521	text	January 2017
A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na ⁺ Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function Beuming, Thijs; Shi, Lei; Javitch, Jonathan A. Molecular Pharmacology, Vol. 70, Issue 5 https://doi.org/10.1124/mol.106.026120	journal	July 2006
Dopamine Transporter Phosphorylation Site Threonine 53 Regulates Substrate Reuptake and Amphetamine-stimulated Efflux Foster, James D.; Yang, Jae-Won; Moritz, Amy E. Journal of Biological Chemistry, Vol. 287, Issue 35 https://doi.org/10.1074/jbc.M112.367706	journal	June 2012
Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT Cremona, M. Laura; Matthies, Heinrich J. G.; Pau, Kelvin Nature Neuroscience, Vol. 14, Issue 4 https://doi.org/10.1038/nn.2781	journal	March 2011
Membrane cholesterol access into a G-protein-coupled receptor Guixà-González, Ramon; Albasanz, José L.; Rodriguez-Espigares, Ismael Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/ncomms14505	journal	February 2017
Independent component analysis: algorithms and applications Hyvärinen, A.; Oja, E. Neural Networks, Vol. 13, Issue 4-5 https://doi.org/10.1016/S0893-6080(00)00026-5	journal	June 2000
Dysregulation of Dopamine Transporters via Dopamine D2 Autoreceptors Triggers Anomalous Dopamine Efflux Associated with Attention-Deficit Hyperactivity Disorder Bowton, E.; Saunders, C.; Erreger, K. Journal of Neuroscience, Vol. 30, Issue 17 https://doi.org/10.1523/jneurosci.5094-09.2010	journal	April 2010
Complete Mapping of Substrate Translocation Highlights the Role of LeuT N-terminal Segment in Regulating Transport Cycle Cheng, Mary Hongying; Bahar, Ivet PLoS Computational Biology, Vol. 10, Issue 10 https://doi.org/10.1371/journal.pcbi.1003879	journal	October 2014
Syntaxin 1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux Binda, Francesca; Dipace, Concetta; Bowton, Erica Molecular Pharmacology, Vol. 74, Issue 4 https://doi.org/10.1124/mol.108.048447	journal	July 2008
Stochastic steps in secondary active sugar transport Adelman, Joshua L.; Ghezzi, Chiara; Bisignano, Paola Proceedings of the National Academy of Sciences, Vol. 113, Issue 27 https://doi.org/10.1073/pnas.1525378113	journal	June 2016
Evaluating the Effects of Cutoffs and Treatment of Long-range Electrostatics in Protein Folding Simulations Piana, Stefano; Lindorff-Larsen, Kresten; Dirks, Robert M. PLoS ONE, Vol. 7, Issue 6 https://doi.org/10.1371/journal.pone.0039918	journal	June 2012
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Neurotransmitter transporters: molecular function of important drug targets Gether, U.; Andersen, P.; Larsson, O. Trends in Pharmacological Sciences, Vol. 27, Issue 7 https://doi.org/10.1016/j.tips.2006.05.003	journal	July 2006
Functional mechanisms of neurotransmitter transporters regulated by lipid–protein interactions of their terminal loops Khelashvili, George; Weinstein, Harel Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1848, Issue 9 https://doi.org/10.1016/j.bbamem.2015.03.025	journal	September 2015
Phosphorylation mechanisms in dopamine transporter regulation Foster, James D.; Vaughan, Roxanne A. Journal of Chemical Neuroanatomy, Vol. 83-84 https://doi.org/10.1016/j.jchemneu.2016.10.004	journal	October 2017
Scalable molecular dynamics with NAMD Phillips, James C.; Braun, Rosemary; Wang, Wei Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802 https://doi.org/10.1002/jcc.20289	journal	January 2005
Spontaneous Inward Opening of the Dopamine Transporter Is Triggered by PIP ₂ -Regulated Dynamics of the N-Terminus Khelashvili, George; Stanley, Nathaniel; Sahai, Michelle A. ACS Chemical Neuroscience, Vol. 6, Issue 11 https://doi.org/10.1021/acschemneuro.5b00179	journal	August 2015
A coarse graining method for the identification of transition rates between molecular conformations Kube, Susanna; Weber, Marcus The Journal of Chemical Physics, Vol. 126, Issue 2 https://doi.org/10.1063/1.2404953	journal	January 2007
Chloride binding site of neurotransmitter sodium symporters Kantcheva, A. K.; Quick, M.; Shi, L. Proceedings of the National Academy of Sciences, Vol. 110, Issue 21 https://doi.org/10.1073/pnas.1221279110	journal	May 2013
Robust Perron cluster analysis in conformation dynamics Deuflhard, Peter; Weber, Marcus Linear Algebra and its Applications, Vol. 398 https://doi.org/10.1016/j.laa.2004.10.026	journal	March 2005
Phosphorylation of Dopamine Transporter Serine 7 Modulates Cocaine Analog Binding Moritz, Amy E.; Foster, James D.; Gorentla, Balachandra K. Journal of Biological Chemistry, Vol. 288, Issue 1 https://doi.org/10.1074/jbc.M112.407874	journal	November 2012
Reactive flux and folding pathways in network models of coarse-grained protein dynamics Berezhkovskii, Alexander; Hummer, Gerhard; Szabo, Attila The Journal of Chemical Physics, Vol. 130, Issue 20 https://doi.org/10.1063/1.3139063	journal	May 2009
Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate Buchmayer, F.; Schicker, K.; Steinkellner, T. Proceedings of the National Academy of Sciences, Vol. 110, Issue 28 https://doi.org/10.1073/pnas.1220552110	journal	June 2013
Mechanisms of dopamine transporter regulation in normal and disease states Vaughan, Roxanne A.; Foster, James D. Trends in Pharmacological Sciences, Vol. 34, Issue 9 https://doi.org/10.1016/j.tips.2013.07.005	journal	September 2013
Molecular Simulation of ab Initio Protein Folding for a Millisecond Folder NTL9(1−39) Voelz, Vincent A.; Bowman, Gregory R.; Beauchamp, Kyle Journal of the American Chemical Society, Vol. 132, Issue 5 https://doi.org/10.1021/ja9090353	journal	February 2010
MSMBuilder2: Modeling Conformational Dynamics on the Picosecond to Millisecond Scale Beauchamp, Kyle A.; Bowman, Gregory R.; Lane, Thomas J. Journal of Chemical Theory and Computation, Vol. 7, Issue 10 https://doi.org/10.1021/ct200463m	journal	August 2011
Allosteric Mechanisms of Molecular Machines at the Membrane: Transport by Sodium-Coupled Symporters LeVine, Michael V.; Cuendet, Michel A.; Khelashvili, George Chemical Reviews, Vol. 116, Issue 11 https://doi.org/10.1021/acs.chemrev.5b00627	journal	February 2016
Everything you wanted to know about Markov State Models but were afraid to ask Pande, Vijay S.; Beauchamp, Kyle; Bowman, Gregory R. Methods, Vol. 52, Issue 1 https://doi.org/10.1016/j.ymeth.2010.06.002	journal	September 2010
Microseconds Simulations Reveal a New Sodium-binding Site and the Mechanism of Sodium-coupled Substrate Uptake by LeuT Zomot, Elia; Gur, Mert; Bahar, Ivet Journal of Biological Chemistry, Vol. 290, Issue 1 https://doi.org/10.1074/jbc.m114.617555	journal	November 2014
ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale Harvey, M. J.; Giupponi, G.; Fabritiis, G. De Journal of Chemical Theory and Computation, Vol. 5, Issue 6 https://doi.org/10.1021/ct9000685	journal	May 2009
Stepwise gating of the Sec61 protein-conducting channel by Sec63 and Sec62 Itskanov, Samuel; Kuo, Katie M.; Gumbart, James C. Nature Structural & Molecular Biology, Vol. 28, Issue 2 https://doi.org/10.1038/s41594-020-00541-x	journal	January 2021
Improvements in Markov State Model Construction Reveal Many Non-Native Interactions in the Folding of NTL9 Schwantes, Christian R.; Pande, Vijay S. Journal of Chemical Theory and Computation, Vol. 9, Issue 4 https://doi.org/10.1021/ct300878a	journal	March 2013
The Mechanism of a Neurotransmitter:Sodium Symporter—Inward Release of Na+ and Substrate Is Triggered by Substrate in a Second Binding Site Shi, Lei; Quick, Matthias; Zhao, Yongfang Molecular Cell, Vol. 30, Issue 6 https://doi.org/10.1016/j.molcel.2008.05.008	journal	June 2008
The solute carrier 6 family of transporters: The Solute Carrier Family 6 Bröer, Stefan; Gether, Ulrik British Journal of Pharmacology, Vol. 167, Issue 2 https://doi.org/10.1111/j.1476-5381.2012.01975.x	journal	August 2012
Two Na ⁺ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog Tavoulari, Sotiria; Margheritis, Eleonora; Nagarajan, Anu Journal of Biological Chemistry, Vol. 291, Issue 3 https://doi.org/10.1074/jbc.m115.692012	journal	November 2015
X-ray structure of dopamine transporter elucidates antidepressant mechanism Penmatsa, Aravind; Wang, Kevin H.; Gouaux, Eric Nature, Vol. 503, Issue 7474 https://doi.org/10.1038/nature12533	journal	September 2013
Transient formation of water-conducting states in membrane transporters Li, J.; Shaikh, S. A.; Enkavi, G. Proceedings of the National Academy of Sciences, Vol. 110, Issue 19 https://doi.org/10.1073/pnas.1218986110	journal	April 2013
Structure and Regulatory Interactions of the Cytoplasmic Terminal Domains of Serotonin Transporter Fenollar-Ferrer, Cristina; Stockner, Thomas; Schwarz, Thomas C. Biochemistry, Vol. 53, Issue 33 https://doi.org/10.1021/bi500637f	journal	August 2014
The N Terminus Specifies the Switch between Transport Modes of the Human Serotonin Transporter Kern, Carina; Erdem, Fatma Asli; El-Kasaby, Ali Journal of Biological Chemistry, Vol. 292, Issue 9 https://doi.org/10.1074/jbc.M116.771360	journal	January 2017
Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics Moritz, Amy E.; Rastedt, Danielle E.; Stanislowski, Daniel J. Journal of Biological Chemistry, Vol. 290, Issue 48 https://doi.org/10.1074/jbc.M115.667055	journal	September 2015
Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood Ng, Joanne; Zhen, Juan; Meyer, Esther Brain, Vol. 137, Issue 4 https://doi.org/10.1093/brain/awu022	journal	March 2014
How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters: Role of LeuT in understanding neurotransmitter transporters Penmatsa, Aravind; Gouaux, Eric The Journal of Physiology, Vol. 592, Issue 5 https://doi.org/10.1113/jphysiol.2013.259051	journal	August 2013
The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants Mergy, M. A.; Gowrishankar, R.; Gresch, P. J. Proceedings of the National Academy of Sciences, Vol. 111, Issue 44 https://doi.org/10.1073/pnas.1417294111	journal	October 2014
Dopamine Transporter Amino and Carboxyl Termini Synergistically Contribute to Substrate and Inhibitor Affinities Sweeney, Carolyn G.; Tremblay, Bradford P.; Stockner, Thomas Journal of Biological Chemistry, Vol. 292, Issue 4 https://doi.org/10.1074/jbc.m116.762872	journal	December 2016
Long‐Time Protein Folding Dynamics from Short‐Time Molecular Dynamics Simulations Chodera, John D.; Swope, William C.; Pitera, Jed W. Multiscale Modeling & Simulation, Vol. 5, Issue 4 https://doi.org/10.1137/06065146X	journal	January 2006
Identification of slow molecular order parameters for Markov model construction Pérez-Hernández, Guillermo; Paul, Fabian; Giorgino, Toni The Journal of Chemical Physics, Vol. 139, Issue 1 https://doi.org/10.1063/1.4811489	journal	July 2013
Dopamine transporter expression and transport capacity is regulated by palmitoylation Rastedt, Danielle; Foster, James; Vaughan, Roxanne The FASEB Journal, Vol. 29, Issue S1 https://doi.org/10.1096/fasebj.29.1_supplement.768.4	journal	April 2015

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Understanding phosphoinositides: rare, dynamic, and essential membrane phospholipids Dickson, Eamonn J.; Hille, Bertil Biochemical Journal, Vol. 476, Issue 1 https://doi.org/10.1042/bcj20180022	journal	January 2019
Emerging Diversity in Lipid–Protein Interactions Corradi, Valentina; Sejdiu, Besian I.; Mesa-Galloso, Haydee Chemical Reviews, Vol. 119, Issue 9 https://doi.org/10.1021/acs.chemrev.8b00451	journal	January 2019
Structure and Gating Dynamics of Na+/Cl– Coupled Neurotransmitter Transporters Joseph, Deepthi; Pidathala, Shabareesh; Mallela, Aditya Kumar Frontiers in Molecular Biosciences, Vol. 6 https://doi.org/10.3389/fmolb.2019.00080	journal	September 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Life Sciences & Biomedicine
Dopamine transport
SLC6 neurotransmitter transporters
Evolutionary gain of function
Molecular dynamics simulations
Markov state models
Reverse transport
SERT
Regulation by PIP2
Regulation by phosphorylation
posttranslational modifications

Additional file 2: of How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties Razavi, Asghar; Khelashvili, George; Weinstein, Harel https://doi.org/10.6084/m9.figshare.5985703 The current record is supplemented by this text	text	January 2018
How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties Razavi, Asghar; Khelashvili, George; Weinstein, Harel https://doi.org/10.6084/m9.figshare.c.4032235.v1 The current record is supplemented by this collection	collection	January 2018
Additional file 1: of How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties Razavi, Asghar; Khelashvili, George; Weinstein, Harel https://doi.org/10.6084/m9.figshare.5985682 The current record is supplemented by this text	text	January 2018
Additional file 1: of How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties Razavi, Asghar; Khelashvili, George; Weinstein, Harel https://doi.org/10.6084/m9.figshare.5985682.v1 The current record is supplemented by this text	text	January 2018
How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties Razavi, Asghar; Khelashvili, George; Weinstein, Harel https://doi.org/10.6084/m9.figshare.c.4032235 The current record is supplemented by this collection	collection	January 2018
Additional file 2: of How structural elements evolving from bacterial to human SLC6 transporters enabled new functional properties Razavi, Asghar; Khelashvili, George; Weinstein, Harel https://doi.org/10.6084/m9.figshare.5985703.v1 The current record is supplemented by this text	text	January 2018