Glut3: Difference between revisions
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==Facilitated Glucose Transporter 3, Solute Carrier Family 2 (GLUT3/ SLC2A3) in Homo Sapiens== | ==Facilitated Glucose Transporter 3, Solute Carrier Family 2 (GLUT3/ SLC2A3) in Homo Sapiens== | ||
<StructureSection load='5c65' size='340' side='right' caption=' | <StructureSection load='5c65' size='340' side='right' caption='Human glucose transporter complex with cholesterol derivative (PDB code [[5c65]])'> | ||
== Function == | == Function == | ||
GLUT3 is one of fourteen facilitative sugar transporters, which use the glucose diffusion gradient to move across various plasma membranes to display various specificities, kinetics and tissue expression profiles <ref name="three">Long, W., & Cheeseman, C. I. (2015). Structure of, and functional insight into the GLUT family of membrane transporters. Cell Health and Cytoskeleton, 7, 167-183. doi:10.2147/CHC.S60484</ref>. Glucose transporters are approximately 500 amino acids in length and part of a growing superfamily of integral membrane glycoproteins that have 12 transmembrane (TM) helices. The transmembrane regions presumably create channels through which glucose can move<ref name="four">Kipmen-Korgun, D., Bilmen-Sarikcioglu, S., Altunbas, H., Demir, R., & Korgun, E. T. (2009). Type-2 diabetes down-regulates glucose transporter proteins and genes of the human blood leukocytes.Scandinavian Journal of Clinical and Laboratory Investigation, 69(3), 350-358. | GLUT3 is one of fourteen facilitative sugar transporters, which use the glucose diffusion gradient to move across various plasma membranes to display various specificities, kinetics and tissue expression profiles <ref name="three">Long, W., & Cheeseman, C. I. (2015). Structure of, and functional insight into the GLUT family of membrane transporters. Cell Health and Cytoskeleton, 7, 167-183. doi:10.2147/CHC.S60484</ref>. Glucose transporters are approximately 500 amino acids in length and part of a growing superfamily of integral membrane glycoproteins that have 12 transmembrane (TM) helices. The transmembrane regions presumably create channels through which glucose can move<ref name="four">Kipmen-Korgun, D., Bilmen-Sarikcioglu, S., Altunbas, H., Demir, R., & Korgun, E. T. (2009). Type-2 diabetes down-regulates glucose transporter proteins and genes of the human blood leukocytes.Scandinavian Journal of Clinical and Laboratory Investigation, 69(3), 350-358. | ||
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==Structure== | ==Structure== | ||
GLUT3(<scene name='71/716527/5c65/1'>5c65</scene>) is a transport protein consisting of 481 amino acids and weighing 52,520 Daltons in its asymmetrical unit<ref name="nineteen">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/</ref>. This protein is an alpha-helical protein consisting of two chains, two different ligands and water<ref name="nineteen"/>. The structure was determined by X-Ray diffraction and was measured at a resolution of 2.65 Angstroms<ref name="twentytwo">http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c65</ref>. GLUT3 consists of 12 transmembrane segments (TMs) folded “into the N-terminal and C-terminal domains, each comprising ‘3+3’ inverted repeats”<ref name="nine"/> These TMs consist of four 3 repeated sections. [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F1.html Here] is a figure by Deng, D., et al. showing these repeated transmembrane segments<ref name="nine">Deng, D., Sun, P., Yan, C., Ke, M., Jiang, X., Xiong, L., . . . Yan, N. (2015). Molecular basis of ligand recognition and transport by glucose transporters. Nature, 526(7573), 391-396. doi:10.1038/nature14655</ref>. The protein consists of two different ligands, Y01 and 37X<ref name="eighteen">http://www.rcsb.org/pdb/explore.do?structureId=5C65</ref>. Octyl Glucose Neopentyl Glycol (<scene name='71/716528/37x/ | GLUT3(<scene name='71/716527/5c65/1'>5c65</scene>) is a transport protein consisting of 481 amino acids and weighing 52,520 Daltons in its asymmetrical unit<ref name="nineteen">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/</ref>. This protein is an alpha-helical protein consisting of two chains, two different ligands and water<ref name="nineteen"/>. The structure was determined by X-Ray diffraction and was measured at a resolution of 2.65 Angstroms<ref name="twentytwo">http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c65</ref>. GLUT3 consists of 12 transmembrane segments (TMs) folded “into the N-terminal and C-terminal domains, each comprising ‘3+3’ inverted repeats”<ref name="nine"/> These TMs consist of four 3 repeated sections. [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F1.html Here] is a figure by Deng, D., et al. showing these repeated transmembrane segments<ref name="nine">Deng, D., Sun, P., Yan, C., Ke, M., Jiang, X., Xiong, L., . . . Yan, N. (2015). Molecular basis of ligand recognition and transport by glucose transporters. Nature, 526(7573), 391-396. doi:10.1038/nature14655</ref>. The protein consists of two different ligands, Y01 and 37X<ref name="eighteen">http://www.rcsb.org/pdb/explore.do?structureId=5C65</ref>. Octyl Glucose Neopentyl Glycol (<scene name='71/716528/37x/2'>37X</scene>) has a chemical formula of C<sub>27</sub>H<sub>52</sub>O<sub>12</sub> and a molecular weight of 569 Da. There are six 37X (501-506a) bound to chain A of 5c65. These ligands are kept in place by hydrogen bonds to arginine, proline, and serine and by van der Waals forces. Chain B has three 37X ligands attached to it (501-503b). These are attached through hydrogen bonds by arginine, proline, and serine as well as by van der Waals forces<ref name="twenty">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/bound/37X</ref>. To view 37X in 3D use [http://www.rcsb.org/pdb/explore/jmol.do?structureId=5C65&residueNr=37X JSmol]. Cholesterol hemisuccinate (<scene name='71/716528/Y01/1'>Y01</scene>) has a chemical formula of C<sub>31</sub>H<sub>50</sub>O<sub>4</sub> and has a molecular weight of 487 Da. One Y01 is attached to chain a and another Y01 is attached to chain b<ref name="twentyone">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/bound/Y01</ref>. To view Y01 in 3D use [http://www.rcsb.org/pdb/explore/jmol.do?structureId=5C65&residueNr=Y01 JSmol]. GLUT3 was also identified and analyzed in a complex with alpha & beta d-glucose. This model was reported with a resolution of 1.5 Å and was in an open-occluded state<ref name="nine"/>. The alpha and beta d glucose were coordinated in a <scene name='71/716528/Binding_pocket/8'>binding pocket</scene> by amino acids N315, E378, Q159, W368, Q280, Q281, N286. These are located on TM8 and TM10a and TM10b<ref name="nine"/>. A figure of this glucose coordination by Deng, D., et al. is available [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F2.html here]. GLUT3 structure was also determined when bound to maltose in an outward-open and an outward-occluded conformation. This was measure to a resolution of 2.6 Å and 2.4 Å respectively. A figure of this maltose coordination by Deng, D., et al. is available [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F3.html here]. To get a better view of the structure of the protein use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5C65 FirstGlance]. | ||
This is 5c65 shown with <scene name="/12/3456/Sample/1">colored groups</scene>. This is 5c65 shown as a <scene name="/12/3456/Sample/2">transparent representation</scene> of the protein. | This is 5c65 shown with <scene name="/12/3456/Sample/1">colored groups</scene>. This is 5c65 shown as a <scene name="/12/3456/Sample/2">transparent representation</scene> of the protein. | ||
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Higher glucose concentration, as seen in diabetics, influences GLUT expression in leukocytes. Patients with type 2 diabetes have decreased GLUT3 in granulocytes, lymphocytes, and monocytes. In addition, the level of transcripts that encode GLUT3 are reduced in diabetic patients. Decreased expression of GLUT3 and other GLUT isoforms could possibly impair immune function and increase susceptibility to infection in type 2 diabetes<ref name="four"/>. | Higher glucose concentration, as seen in diabetics, influences GLUT expression in leukocytes. Patients with type 2 diabetes have decreased GLUT3 in granulocytes, lymphocytes, and monocytes. In addition, the level of transcripts that encode GLUT3 are reduced in diabetic patients. Decreased expression of GLUT3 and other GLUT isoforms could possibly impair immune function and increase susceptibility to infection in type 2 diabetes<ref name="four"/>. | ||
===Alzheimer's Disease=== | ===Alzheimer's Disease=== | ||
Alzheimer’s disease shows levels of impaired glucose uptake and metabolism, which leads | Alzheimer’s disease shows levels of impaired glucose uptake and metabolism, which leads to neurodegeneration via down-regulation of many other factors in the brain. GLUT3 is responsible for transporting glucose from extracellular space to neuronal tissue, specifically dendrites and axons. Decreased levels of GLUT3 in Alzheimer brain shows a positive correlation to decreased levels of N-acetylglucosamine, which is a derivative of glucose. The impaired presence of GLUT3 leads to hyperphosphorylation of the Tau protein, which normally stabilizes neuronal microtubules. Lastly there is a reduction in the transcription for factor hypoxia-inducible factor 1, which plays a role in glucose metabolism in the brain. The comparison between a normal healthy brain and an Alzheimer brain revealed that there was a 25-30% decrease in GLUT3 levels in the Alzheimer brain<ref name="eight"/>. | ||
===Huntington’s Disease=== | ===Huntington’s Disease=== | ||
Huntington’s disease leads to decreased expression of GLUT3 in the plasma membrane. Increasing the expression of GLUT3 in a Huntington’s disease brain can delay the onset of the disease<ref name="ten">Vittori, A., Breda, C., Repici, M., Orth, M., Roos, R. A. C., Outeiro, T. F., . . . the REGISTRY investigators of the European Huntington's Disease Network. (2014). Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in huntington's disease. Human Molecular Genetics, 23(12), 3129-3137. doi:10.1093/hmg/ddu022</ref>. Rab11 is a protein that is involved with the regulation of transporter trafficking. It helps in the regulation of glucose transporters particularly the GLUT3 transporter. Its regulation is impaired by Huntington’s disease, which leads to the decreased cell surface expression of GLUT3 in the brain. The exact mechanism of Huntington’s disease is still unknown to this day<ref name="eleven">McClory, H., Williams, D., & Sapp, E. (2014). Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice. Acta Neuropathol Commun, 2, 1-9.</ref>. | Huntington’s disease leads to decreased expression of GLUT3 in the plasma membrane. Increasing the expression of GLUT3 in a Huntington’s disease brain can delay the onset of the disease<ref name="ten">Vittori, A., Breda, C., Repici, M., Orth, M., Roos, R. A. C., Outeiro, T. F., . . . the REGISTRY investigators of the European Huntington's Disease Network. (2014). Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in huntington's disease. Human Molecular Genetics, 23(12), 3129-3137. doi:10.1093/hmg/ddu022</ref>. Rab11 is a protein that is involved with the regulation of transporter trafficking. It helps in the regulation of glucose transporters particularly the GLUT3 transporter. Its regulation is impaired by Huntington’s disease, which leads to the decreased cell surface expression of GLUT3 in the brain. The exact mechanism of Huntington’s disease is still unknown to this day<ref name="eleven">McClory, H., Williams, D., & Sapp, E. (2014). Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice. Acta Neuropathol Commun, 2, 1-9.</ref>. | ||
== 3D structure of sugar transporters == | |||
See [[ABC transporter]] | |||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||