Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family

Custódio, Tânia F.; Paulsen, Peter Aasted; Frain, Kelly M.; Pedersen, Bjørn Panyella

doi:10.26508/lsa.202000858

Cited by 37 publications

(24 citation statements)

References 48 publications

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“…Considering the high degree of identity between the GLUT3 and GLUT14 genes, it is likely that GLUT3 transcripts were mistaken as GLUT14, as in our current study. In any case, a hypoxia-induced switch to GLUT3 as the preferred glucose transporter is consistent with the observations that GLUT3 is found in neurons and other cell types with high energy demands and has greater affinity for glucose compared to GLUT1 [79,80].…”

Section: Discussionsupporting

confidence: 89%

GLUT3/SLC2A3 Is an Endogenous Marker of Hypoxia in Prostate Cancer Cell Lines and Patient-Derived Xenograft Tumors

et al. 2022

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The microenvironment of solid tumors is dynamic and frequently contains pockets of low oxygen levels (hypoxia) surrounded by oxygenated tissue. Indeed, a compromised vasculature is a hallmark of the tumor microenvironment, creating both spatial gradients and temporal variability in oxygen availability. Notably, hypoxia associates with increased metastasis and poor survival in patients. Therefore, to aid therapeutic decisions and better understand hypoxia’s role in cancer progression, it is critical to identify endogenous biomarkers of hypoxia to spatially phenotype oncogenic lesions in human tissue, whether precancerous, benign, or malignant. Here, we characterize the glucose transporter GLUT3/SLC2A3 as a biomarker of hypoxic prostate epithelial cells and prostate tumors. Transcriptomic analyses of non-tumorigenic, immortalized prostate epithelial cells revealed a highly significant increase in GLUT3 expression under hypoxia. Additionally, GLUT3 protein increased 2.4-fold in cultured hypoxic prostate cell lines and was upregulated within hypoxic regions of xenograft tumors, including two patient-derived xenografts (PDX). Finally, GLUT3 out-performs other established hypoxia markers; GLUT3 staining in PDX specimens detects 2.6–8.3 times more tumor area compared to a mixture of GLUT1 and CA9 antibodies. Therefore, given the heterogeneous nature of tumors, we propose adding GLUT3 to immunostaining panels when trying to detect hypoxic regions in prostate samples.

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Section: Discussionsupporting

confidence: 89%

GLUT3/SLC2A3 Is an Endogenous Marker of Hypoxia in Prostate Cancer Cell Lines and Patient-Derived Xenograft Tumors

et al. 2022

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“…As expected for an MFS-fold transporter [4,66,69,70], N-and C-domains exhibited pseudo-symmetry perpendicularly to the plane of the membrane (Figure 1A). The present model revealed at least 6 intracellular helices (ICHs, Figure 1A&B), as observed in the AF2 model [34] and other experimentally resolved mammalians MFS transporters (e.g., GLUT1/SLC2A1, GLUT3/SLC2A3, GLUT5/SLCA5) [49,71,72]. These ICHs are in close contact with TMHs for which local details are discussed in section 3.2.…”

Section: Topological Overview Of the Hoat1 Modelsupporting

confidence: 77%

Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes

Janaszkiewicz

Tóth

Faucher

et al. 2022

Preprint

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The human SLC22A6/OAT1 plays an important role in the disposition of a broad range of endogenous substances and xenobiotics. This is particularly important from the pharmacological point of view since OAT1 is involved in drug elimination events. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about OAT1 structure and the transport mechanism at the atomic level remains fragmented owing to the lack of resolved structures. By means of protein-threading modeling refined by μs-scaled Molecular Dynamics simulations, the present study provides the first robust model of hOAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of hOAT1 in inward-facing conformation, we here provide the essential structural and functional features comparing both states. The intracellular motifs conserved among Major Facilitator Superfamily members create a so-called "charge-relay system" that works as molecular switches modulating the conformation. The principal element of the event points at interactions charged residues that appear crucial for the transporter dynamics and function. Besides, hOAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein. MD simulations supported the pivotal role of phosphatidylethanolamine (PE) components on the protein conformation stability. The present model is made available to decipher the impact of any observed polymorphism and mutation on drug transport as well as to understand substrate binding modes.

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“… 259 Consistent with this rationale, recent mutagenesis between GLUT1 and GLUT3 in Xenopous oocytes have shown that their turnover rates are changed by selective mutations to the intracellular salt bridge forming residues. 259 Moreover, a bound chloride ion was found to coordinate residues between N-terminal salt bridge interactions of GLUT1 and STP10 in the inward-facing structures, 254 , 259 implying a potential allosteric site. In a similar manner, GLUT activities are thought to be dependent on anionic lipids because their negatively charged headgroups can compete for interbundle salt bridge formation to facilitate salt bridge breakage.…”

Section: The Alternating-access Mechanism Of Glucose (Glut) Transportmentioning

confidence: 86%

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

et al. 2021

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The major facilitator superfamily (MFS) is the largest known superfamily of secondary active transporters. MFS transporters are responsible for transporting a broad spectrum of substrates, either down their concentration gradient or uphill using the energy stored in the electrochemical gradients. Over the last 10 years, more than a hundred different MFS transporter structures covering close to 40 members have provided an atomic framework for piecing together the molecular basis of their transport cycles. Here, we summarize the remarkable promiscuity of MFS members in terms of substrate recognition and proton coupling as well as the intricate gating mechanisms undergone in achieving substrate translocation. We outline studies that show how residues far from the substrate binding site can be just as important for fine-tuning substrate recognition and specificity as those residues directly coordinating the substrate, and how a number of MFS transporters have evolved to form unique complexes with chaperone and signaling functions. Through a deeper mechanistic description of glucose (GLUT) transporters and multidrug resistance (MDR) antiporters, we outline novel refinements to the rocker-switch alternating-access model, such as a latch mechanism for proton-coupled monosaccharide transport. We emphasize that a full understanding of transport requires an elucidation of MFS transporter dynamics, energy landscapes, and the determination of how rate transitions are modulated by lipids.

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Structural comparison of GLUT1 to GLUT3 reveal transport regulation mechanism in sugar porter family

Cited by 37 publications

References 48 publications

GLUT3/SLC2A3 Is an Endogenous Marker of Hypoxia in Prostate Cancer Cell Lines and Patient-Derived Xenograft Tumors

GLUT3/SLC2A3 Is an Endogenous Marker of Hypoxia in Prostate Cancer Cell Lines and Patient-Derived Xenograft Tumors

Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

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