Membrane Phase-Dependent Occlusion of Intramolecular GLUT1 Cavities Demonstrated by Simulations

Iglésias-Fernández, Javier; Quinn, Peter J.; Naftalin, Richard J; Domene, Carmen

doi:10.1016/j.bpj.2017.01.030

Cited by 12 publications

(24 citation statements)

References 52 publications

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“…630 The simulations of two opposite protein conformations showed how the protein responds to different lipid environments, as in the gel phase the access to the central glucose binding site becomes narrower, with no continuous pathway from the extracellular to the intracellular side. 630 CG simulations have provided a first characterization of the lipid distribution around the transporter embedded in a complex mixture, showing an enrichment of polyunsaturated and fully saturated lipids in the lower and upper leaflet, respectively. 121 As the activity of GLUTs is regulated by the composition of the membrane, molecular simulations in the future are expected to yield further insight into the specificity of such interactions, especially with anionic lipids and cone-shaped lipids.…”

Section: Slc Transportersmentioning

confidence: 99%

Emerging Diversity in Lipid–Protein Interactions

et al. 2019

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Membrane lipids interact with proteins in a variety of ways, ranging from providing a stable membrane environment for proteins to being embedded in to detailed roles in complicated and well-regulated protein functions. Experimental and computational advances are converging in a rapidly expanding research area of lipid–protein interactions. Experimentally, the database of high-resolution membrane protein structures is growing, as are capabilities to identify the complex lipid composition of different membranes, to probe the challenging time and length scales of lipid–protein interactions, and to link lipid–protein interactions to protein function in a variety of proteins. Computationally, more accurate membrane models and more powerful computers now enable a detailed look at lipid–protein interactions and increasing overlap with experimental observations for validation and joint interpretation of simulation and experiment. Here we review papers that use computational approaches to study detailed lipid–protein interactions, together with brief experimental and physiological contexts, aiming at comprehensive coverage of simulation papers in the last five years. Overall, a complex picture of lipid–protein interactions emerges, through a range of mechanisms including modulation of the physical properties of the lipid environment, detailed chemical interactions between lipids and proteins, and key functional roles of very specific lipids binding to well-defined binding sites on proteins. Computationally, despite important limitations, molecular dynamics simulations with current computer power and theoretical models are now in an excellent position to answer detailed questions about lipid–protein interactions.

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Section: Slc Transportersmentioning

confidence: 99%

Emerging Diversity in Lipid–Protein Interactions

et al. 2019

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“…The obtained GluT1 structure inspired the development of the molecular models aiming to elucidate the different aspects of the GluT1 solute transfer 19–22 . The glucose pathway through the transporter was predicted using the combination of targeted dynamics to reproduce the protein conformational transition and steered dynamics inducing translocation of the solute 19 .…”

Section: Introductionmentioning

confidence: 99%

New insights into GluT1 mechanics during glucose transfer

Galochkina

Chong

Challali

et al. 2019

Sci Rep

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Glucose plays a crucial role in the mammalian cell metabolism. In the erythrocytes and endothelial cells of the blood-brain barrier, glucose uptake is mediated by the glucose transporter type 1 (GluT1). GluT1 deficiency or mutations cause severe physiological disorders. GluT1 is also an important target in cancer therapy as it is overexpressed in tumor cells. Previous studies have suggested that GluT1 mediates solute transfer through a cycle of conformational changes. However, the corresponding 3D structures adopted by the transporter during the transfer process remain elusive. In the present work, we first elucidate the whole conformational landscape of GluT1 in the absence of glucose, using long molecular dynamics simulations and show that the transitions can be accomplished through thermal fluctuations. Importantly, we highlight a strong coupling between intracellular and extracellular domains of the protein that contributes to the transmembrane helices reorientation during the transition. The conformations adopted during the simulations differ from the known 3D bacterial homologs structures resolved in similar states. In holo state simulations, we find that glucose transits along the pathway through significant rotational motions, while maintaining hydrogen bonds with the protein. These persistent motions affect side chains orientation, which impacts protein mechanics and allows glucose progression.

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“…When the protein was embedded in the gel phase membrane, the dimensions of the intramolecular pathways were reduced (Iglesias-Fernandez et al. 2017). The maximum value of the bottleneck radius found in the inward-facing branch of the pathway, in either the gel or fluid phase, permits the passage of glucose molecules with a minimal radius of 1.9 Å.…”

Section: Membrane Proteins and Their Regulationmentioning

confidence: 99%

“…It is apparent that membrane fluid to gel transformation compresses of the transporter, as maintaining the transporter temperature at 50 °C, while cooling the membrane lipids to 35 °C had a similar effect to cooling both membrane and transporter to 35 °C (Iglesias-Fernandez et al. 2017 ).…”

Section: Membrane Proteins and Their Regulationmentioning

confidence: 99%