Effect of Dimerization on the Dynamics of Neurotransmitter:Sodium Symporters

Gür, Mert; Cheng, Mary Hongying; Zomot, Elia; Bahar, İvet

doi:10.1021/acs.jpcb.6b09876

Cited by 24 publications

(17 citation statements)

References 69 publications

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“…Our findings that K m appears increased in SNCA -OVX mice in addition to V max , appears to indicate that α-synuclein not only increases the number of DA-translocation sites, but also affects how DA binds to DAT. One candidate explanation might be an underlying change to the stoichiometry of DATs e.g., an increase in monomeric/oligomeric (dimer or tetramer) ratio, which was not assessed here but is known to affect the number of actively translocating DAT units and their availability to bind substrate (Gur et al, 2017 ; Zhen and Reith, 2018 ). Interestingly, cholesterol has been shown to affect how DA binds to DAT by promoting an outward facing confirmation (Hong and Amara, 2010 ; Jones et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of α-Synuclein and Cholesterol

Threlfell

Mohammadi

Ryan

et al. 2021

Front. Cell. Neurosci.

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Striatal dopamine transporters (DAT) powerfully regulate dopamine signaling, and can contribute risk to degeneration in Parkinson’s disease (PD). DATs can interact with the neuronal protein α-synuclein, which is associated with the etiology and molecular pathology of idiopathic and familial PD. Here, we tested whether DAT function in governing dopamine (DA) uptake and release is modified in a human-α-synuclein-overexpressing (SNCA-OVX) transgenic mouse model of early PD. Using fast-scan cyclic voltammetry (FCV) in ex vivo acute striatal slices to detect DA release, and biochemical assays, we show that several aspects of DAT function are promoted in SNCA-OVX mice. Compared to background control α-synuclein-null mice (Snca-null), the SNCA-OVX mice have elevated DA uptake rates, and more pronounced effects of DAT inhibitors on evoked extracellular DA concentrations ([DA]o) and on short-term plasticity (STP) in DA release, indicating DATs play a greater role in limiting DA release and in driving STP. We found that DAT membrane levels and radioligand binding sites correlated with α-synuclein level. Furthermore, DAT function in Snca-null and SNCA-OVX mice could also be promoted by applying cholesterol, and using Tof-SIMS we found genotype-differences in striatal lipids, with lower striatal cholesterol in SNCA-OVX mice. An inhibitor of cholesterol efflux transporter ABCA1 or a cholesterol chelator in SNCA-OVX mice reduced the effects of DAT-inhibitors on evoked [DA]o. Together these data indicate that human α-synuclein in a mouse model of PD promotes striatal DAT function, in a manner supported by extracellular cholesterol, suggesting converging biology of α-synuclein and cholesterol that regulates DAT function and could impact DA function and PD pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of α-Synuclein and Cholesterol

Threlfell

Mohammadi

Ryan

et al. 2021

Front. Cell. Neurosci.

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“…DAT also has a cooperative effect on inhibitor binding and substrate transport in the individual protomers 21 . Supporting this idea, recent simulations indicate that DAT collective motions resemble more the conformational changes associated with transport when it is analyzed as a dimer than as a monomer, suggesting that DAT would be a more efficient transporter in a dimer conformation 22 . Access to the structures of MAT dimers and higher order oligomers at the atomistic resolution appear therefore timely to guide and inspire the design of new experiments.…”

Section: Introductionmentioning

confidence: 90%

Dimer Interface of the Human Serotonin Transporter and Effect of the Membrane Composition

Periole

Zeppelin

Schiøtt

2018

Sci Rep

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The oligomeric state of membrane proteins has recently emerged in many cases as having an effect on their function. However, the intrinsic dynamics of their spatial organization in cells and model systems makes it challenging to characterize. Here we use molecular dynamics (MD) simulations at multiple resolutions to determine the dimer conformation of the human serotonin transporter (hSERT). From self-assembly simulations we predict dimer candidates and subsequently quantify their relative strength. We use umbrella sampling (US) replica exchange MD simulations for which we present extensive analysis of their efficiency and improved sampling compared to regular US MD simulations. The data shows that the most stable hSERT dimer interface is symmetrical and involves transmembrane helix 12 (TM12), similar to the crystal structure of the bacterial homologue LeuT, but with a slightly different orientation. We also describe the supramolecular organization of hSERT from a 250 μs self-assembly simulation. Finally, the effects of the presence of phosphatidylinositol bisphosphate or cholesterol in the membrane model has been quantified for the TM12-TM12 predicted interface. Collectively, the presented data bring new insight to the area of protein and lipid interplay in biological membranes.

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“…In general, the MD simulations of microsecond to millisecond scales are capable of providing principally new information about the movements in molecular systems as it was shown on the bovine pancreatic trypsin inhibitor and archaeal aspartate transporter GltPh systems. The described principal motions were found to overlap with the predictions from an anisotropic network model, and therefore they cannot be accessed by the MD simulations performed in a nanoscale range …”

Section: Introductionmentioning

confidence: 94%

Molecular dynamics insights into protein‐glycosaminoglycan systems from microsecond‐scale simulations

2019

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Heparin is a key player in cell signaling via its physical interactions with protein targets in the extracellular matrix. However, basic molecular level understanding of these highly biologically relevant intermolecular interactions is still incomplete. In this study, for the first time, microsecond-scale MD simulations are reported for a complex between fibroblast growth factor 1 and heparin. We rigorously analyze this molecular system in terms of the conformational space, structural, energetic, and dynamic characteristics. We reveal that the conformational selection mechanism of binding denotes a recognition specificity determinant. We conclude that the length of the simulation could be crucial for evaluation of some of the analyzed parameters. Our data provide novel significant insights into the interactions in the fibroblast growth factor 1 complex with heparin, in particular, and into the physical-chemical nature of protein-glycosaminoglycan systems in general, which have potential applicability for biomaterials development in the area of regenerative medicine. K E Y W O R D Sfibroblast growth factor 1, heparin conformational analysis, molecular dynamics, proteinglycosaminoglycan interactions, ring puckering

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Effect of Dimerization on the Dynamics of Neurotransmitter:Sodium Symporters

Cited by 24 publications

References 69 publications

Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of α-Synuclein and Cholesterol

Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of α-Synuclein and Cholesterol

Dimer Interface of the Human Serotonin Transporter and Effect of the Membrane Composition

Molecular dynamics insights into protein‐glycosaminoglycan systems from microsecond‐scale simulations

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