Structure, function and regulation of mammalian glucose transporters of the SLC2 family
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INVITED REVIEW
Structure, function and regulation of mammalian glucose transporters of the SLC2 family Geoffrey D. Holman 1 Received: 17 January 2020 / Revised: 27 May 2020 / Accepted: 29 May 2020 # The Author(s) 2020
Abstract The SLC2 genes code for a family of GLUT proteins that are part of the major facilitator superfamily (MFS) of membrane transporters. Crystal structures have recently revealed how the unique protein fold of these proteins enables the catalysis of transport. The proteins have 12 transmembrane spans built from a replicated trimer substructure. This enables 4 trimer substructures to move relative to each other, and thereby alternately opening and closing a cleft to either the internal or the external side of the membrane. The physiological substrate for the GLUTs is usually a hexose but substrates for GLUTs can include urate, dehydro-ascorbate and myo-inositol. The GLUT proteins have varied physiological functions that are related to their principal substrates, the cell type in which the GLUTs are expressed and the extent to which the proteins are associated with subcellular compartments. Some of the GLUT proteins translocate between subcellular compartments and this facilitates the control of their function over long- and short-time scales. The control of GLUT function is necessary for a regulated supply of metabolites (mainly glucose) to tissues. Pathophysiological abnormalities in GLUT proteins are responsible for, or associated with, clinical problems including type 2 diabetes and cancer and a range of tissue disorders, related to tissue-specific GLUT protein profiles. The availability of GLUT crystal structures has facilitated the search for inhibitors and substrates and that are specific for each GLUT and that can be used therapeutically. Recent studies are starting to unravel the drug targetable properties of each of the GLUT proteins. Keywords Glucose transport . GLUT proteins . Membrane transport . GLUT1 . GLUT2 . GLUT3 . GLUT4 . GLUT5 . Regulated transport . Insulin . Hypoxia . ATP depletion
Abbreviations GGAP2 Golgi associated, gamma adaptin ear containing, ARF-binding protein 2 VAMP Vesicle-associated membrane protein IRAP Insulin-responsive aminopeptidase UBC9 Polyubiquitin-C precursor 9 USP25 Ubiquitin carboxyl-terminal hydrolase 25 TM Transmembrane segment p115 General vesicular transport factor p115 MSNBA N-[4-(methylsulfonyl)-2nitrophenyl]-1,3-benzodioxol-5-amine TBC Tre-2/Bub2/Cdc16 CHC Clathrin heavy chain
* Geoffrey D. Holman [email protected] 1
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK
ERGIC TGN MVB
ER-Golgi intermediate compartment Trans-Golgi network Multivesicular body
Introduction The SLC (SoLute Carrier) gene family has been classified into 65 sub-families with identities within the sub-family that differ more than 20–25% from other SLCs [38, 89]. The SLC2 sub-families of 14 related genes are thus distinct from the closest relatives (which are the SLC19 sub-family) and lie within the major facilitator superfamily (MFS) group
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