Mammalian Glucose Transporter Activity Is Dependent upon Anionic and Conical Phospholipids

Hresko, Richard C.; Kraft, Thomas E.; Quigley, Andrew; Carpenter, E.P.; Hruz, Paul W.

doi:10.1074/jbc.m116.730168

Cited by 63 publications

(65 citation statements)

References 51 publications

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“…Therefore, much more complex interactions can be expected. In this regard, a recent article by Hresko et al (50) highlighted the activation effect of anionic phospholipids on the turnover rate of GLUT3 and GLUT4 transporters, whereas the substrate affinity remained unaltered, providing evidence of a direct interaction of the studied phospholipids with the transporter. Anionic phospholipids are found exclusively on the endofacial leaflet of mammalian lipid bilayers, thus supporting a crucial role for bilayer composition in transporter activity.…”

Section: Resultsmentioning

confidence: 99%

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

Iglésias-Fernández

Quinn

Naftalin

et al. 2017

Biophysical Journal

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Experimental evidence has shown a close correlation between the composition and physical state of the membrane bilayer and glucose transport activity via the glucose transporter GLUT1. Cooling alters the membrane lipids from the fluid to gel phase, and also causes a large decrease in the net glucose transport rate. The goal of this study is to investigate how the physical phase of the membrane alters glucose transporter structural dynamics using molecular-dynamics simulations. Simulations from an initial fluid to gel phase reduce the size of the cavities and tunnels traversing the protein and connecting the external regions of the transporter and the central binding site. These effects can be ascribed solely to membrane structural changes since in silico cooling of the membrane alone, while maintaining the higher protein temperature, shows protein structural and dynamic changes very similar to those observed with uniform cooling. These results demonstrate that the protein structure is sensitive to the membrane phase, and have implications for how transmembrane protein structures respond to their physical environment.

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Section: Resultsmentioning

confidence: 99%

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

Iglésias-Fernández

Quinn

Naftalin

et al. 2017

Biophysical Journal

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“…There is now ample evidence that lipids can modulate membrane protein function 39, 40 . As seen for lipids such as diacylglycerol 41 , the conical shape of DIM may modulate membrane protein activity. Accordingly, we find that DIM increase the non-opsonic phagocytosis of zymosan, a process well known to be mediated by a repertoire of membrane receptors, including complement receptor 3 (CR3) 32 and the mannose receptor 42 .…”

Section: Discussionmentioning

confidence: 99%

The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages

Augenstreich

Haanappel

Ferré

et al. 2019

Preprint

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24Phthiocerol dimycocerosate (DIM) is a major virulence factor of the pathogen 25 Mycobacterium tuberculosis (Mtb). While this lipid promotes the entry of Mtb into 26 macrophages, which occurs via phagocytosis, its molecular mechanism of action is 27 unknown. Here, we combined biophysical, cell biology, and modelling approaches to 28 reveal the molecular mechanism of DIM action on macrophage membranes leading to 29 the first step of Mtb infection. MALDI-TOF mass spectrometry showed that DIM 30 molecules are transferred from the Mtb envelope to macrophage membranes during 31 infection. Multi-scale molecular modeling and 31 P-NMR experiments revealed that DIM 32 adopts a conical shape in membranes and aggregate in the stalks formed between 33 two opposing lipid bilayers. Infection of macrophages pre-treated with lipids of various 34shapes uncovered a general role for conical lipids in promoting phagocytosis. Taken 35 together, these results reveal how the molecular shape of a mycobacterial lipid can 36 modulate the biological function of macrophages. 37 38 we developed a multidisciplinary approach combining multiscale Molecular Dynamics 73 (MD) simulations, solid-state NMR and cell biology experiments. This revealed how 74 the molecular shape of DIM can affect macrophage membranes to promote 75 phagocytosis. 76 77 78 RESULTS 79 80 DIM are transferred to host cell membranes during macrophage infection 81First, we used MALDI-TOF mass spectrometry to assess whether DIM added 82 to host cells is incorporated into their membranes. Human macrophage (THP-1) cells 83 Figure 1: DIM are transferred from the bacterial envelope to macrophage membranes. (a) Structure of the DIM family of lipids, where m denotes the range of carbon atoms on the phthiocerol moiety, and n and p on the mycocerosate moieties. (b) MALDI-TOF mass spectra of purified DIM and of the membrane fraction of macrophages treated with DIM. (c) MALDI-TOF mass spectra of WT Mtb (HR37v) and of the membrane fraction of macrophages infected by H37Rv or by the H37RvDlppX mutant. M: low intensity peak corresponding to the detection of the matrix molecule in the DIM region of interest. The star symbol highlights the mass of the DIM molecule chosen for the modelling, with m=18, n=17, and p=4.

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“…They do not heed the known facts that the structure and activities of GLUTs are sensitive to the membrane lipid compositions. (52)(53)(54)(55)(56) In particular, glucose transport across erythrocyte membranes was found, long ago, to be reduced by 75% by exposure to phospholipase A2 which hydrolyzes fatty acyl groups from the sn-2 position of glycerophospholipids. (54,56) In general, lipid-protein interactions are significant determinants of the membrane protein functions.…”

Section: Introductionmentioning

confidence: 99%

Quantitative characterization of the path of glucose diffusion facilitated by human glucose transporter 1

Chen

2019

Preprint

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Glucose transporter GLUT1 is ubiquitously expressed in the human body from the red cells to the blood-brain barrier to the skeletal muscles. It is physiologically relevant to understand how GLUT1 facilitates diffusion of glucose across the cell membrane. It is also pathologically relevant because GLUT1 deficiency causes neurological disorders and anemia and because GLUT1 overexpression fuels the abnormal growth of cancer cells. This article presents a quantitative investigation of GLUT1 based on all-atom molecular-dynamics (MD) simulations of the transporter embedded in lipid bilayers of asymmetric inner-and-outerleaflet lipid compositions, subject to asymmetric intra-and-extra-cellular environments. This is in contrast with the current literature of MD studies of the transporter embedded in a symmetric lipid bilayer of a single lipid type. The equilibrium (unbiased) dynamics of GLUT1 shows that it can facilitate glucose diffusion across the cell membrane without undergoing large-scale conformational motions. The Gibbs free-energy profile, which is still lacking in the current literature of GLUT1, quantitatively characterizes the diffusion path of glucose from the periplasm, through an extracellular gate of GLUT1, on to the binding site, and off to the cytoplasm. This transport mechanism is validated by the experimental data that GLUT1 has low water-permeability, high glucose-affinity, uptakeefflux symmetry, and 10 kcal/mol Arrhenius activation barrier around 37°C.

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Mammalian Glucose Transporter Activity Is Dependent upon Anionic and Conical Phospholipids

Cited by 63 publications

References 51 publications

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

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

The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages

Quantitative characterization of the path of glucose diffusion facilitated by human glucose transporter 1

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