GLUT1
From Proteopedia
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There is at least one known amino acid substitution in GLUT1 that can cause GLUT1 deficiency syndrome. <scene name='91/910668/Glut1_arg126_1/1'>Arg126</scene> causes transmembrane helix #4 to become kinked, blocking substrate transport. Arg126 is the amino acid most often mutated in GLUT1 deficiency syndrome.<ref>PMID:18387950</ref> | There is at least one known amino acid substitution in GLUT1 that can cause GLUT1 deficiency syndrome. <scene name='91/910668/Glut1_arg126_1/1'>Arg126</scene> causes transmembrane helix #4 to become kinked, blocking substrate transport. Arg126 is the amino acid most often mutated in GLUT1 deficiency syndrome.<ref>PMID:18387950</ref> | ||
| - | GLUT1, and other glucose transporters, have an <scene name='91/910668/Ich_domain_1/1'>intracellular helices (ICH) domain</scene>. The ICH domain of GLUT1 may play a role in stabilizing the outward-facing conformation of the enzyme based on computer modeling in [https://en.wikipedia.org/wiki/MODELLER MODELLER].<ref>PMID:25919356</ref> Two residues of interest in the ICH domain are Arg212 and Asp240. These residues are hypothesized to participate in hydrogen | + | GLUT1, and other glucose transporters, have an <scene name='91/910668/Ich_domain_1/1'>intracellular helices (ICH) domain</scene>. The ICH domain of GLUT1 may play a role in stabilizing the outward-facing conformation of the enzyme based on computer modeling in [https://en.wikipedia.org/wiki/MODELLER MODELLER].<ref>PMID:25919356</ref> Two residues of interest in the ICH domain are Arg212 and Asp240. These residues are hypothesized to participate in hydrogen bonding between the ICH domain and transmembrane domains of the protein with the cumulative effect of stabilizing the outward-facing conformation. |
== References == | == References == | ||
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Revision as of 06:38, 3 May 2022
Facilitated Glucose Transporter 1, Solute Carrier Family 2, Homo sapiens
ClassificationGLUT proteins, encoded by the SLC2 genes, are part of the Major Facilitator Superfamily (MFS) of substrate transporters. Structural elements characteristic of GLUT proteins are twelve transmembrane domains, one N-linked glycosylation site, and lengths of about five-hundred amino acids.[1] GLUT proteins transport a variety of monosaccharides that enable cellular respiration and are thus abundant in the body. Referencing the CATH classification database, the MFS superfamily has 23,982 unique species and 134 characteristic domains. GLUT1 has two highly-conserved ATP-binding domains known as Walker motifs A and B.[2] A third ATP-binding domain is less conserved. According to UniProt, these specific sequences in the GLUT1 transporter are shared among glucose transporters in several different organisms.
FunctionGLUT1 is a glucose transporter expressed by all cells in the body to maintain adequate baseline glucose uptake. Some examples of tissues that express GLUT1 at high rates include: the placenta and fetal tissues, epithelial cells of the retina and mammary gland, and the brain.[3] BrainThe GLUT1 transporter works synergistically with other solute carriers in the brain. Astrocytes and endothelial cells of brain capillaries primarily express GLUT1; neurons primarily express Glut3. GLUT1 has a relatively high Km and is upregulated in times of hypoglycemia in the brain to ensure adequate glucose uptake. Glut3 has a low Km to ensure a steady supply of glucose for neurons even when extracellular glucose concentrations are low.[4] Astrocytes are cells of the brain that enable glycogen storage; as a result, they are of great metabolic importance in brain function. GLUT1, Glut3, and monocarboxylate transporters (MCTs) work in conjunction to regulate transport of energy-providing molecules such as glucose and lactate in the brain.[5]
PregnancyThe GLUT1 transporter is highly expressed in both the placenta and the developing embryo/fetus.[6] During pregnancy, there is no significant fetal gluconeogenesis in humans.[7] High GLUT1 expression in the fetoplacental tissues ensures that the fetus receives a steady supply of glucose. RetinaGLUT1 is the most abundant glucose transporter in the retina. Retinal pigmented epithelium and retinal capillary endothelium, the tissues that comprise the retina-brain barrier, express GLUT1.[8] The retina has a consistently high energy requirement due to abundance of energy-consuming enzymes such as Sodium-Potassium ATPase. Studies on mice have shown that GLUT1 knockout leads to photoreceptor cell death - a greater effect was noted in cone cells versus rod cells.[9] DiseaseGLUT1 Deficiency SyndromeGLUT1 deficiency syndrome is a autosomal-dominant genetic condition which involves a mutation in SLC2A1, the gene that codes for the GLUT1 transporter. Symptoms of GLUT1 deficiency syndrome develop within the first few months of life and manifest themselves neurologically. Symptoms can include seizures, involuntary eye movements, microcephaly, developmental delays, intellectual disabilities, spasticity, or ataxia.[10] CancerOncogenes such as Ras and Src have been linked to upregulation of GLUT1 in rat tumors. Many studies have shown that GLUT1 is upregulated in malignancies of the breast.[11] Upregulation of the GLUT1 transporter has been shown to increase cell proliferation in some types of breast cancer.[12] GLUT1 upregulation is thought to play a role in malignant cell proliferation in some types of tumors.[13] DiabetesDiabetes and PregnancyGLUT1 has been shown to be upregulated in the placental tissue of mothers with both pregestational and gestational diabetes, even when the mother's glycemic control is considered good. It is hypothesized that fetal hyperglycemia due to increased glucose transporter expression increases the risk of offspring developing type I or type II diabetes.[14] Diabetic RetinopathyGLUT1 has been found to be upregulated in retinal tissue of diabetic mice. Studies on mice show that GLUT1 overexpression plays a key role in development of diabetic retinopathy.[15] While it has been proven that hyperglycemia causes diabetic retinopathy in humans, at this point more research is necessary to determine if GLUT1 plays a direct role in diabetic retinopathy. Alzheimer's DiseaseA handful of glucose transporters, including GLUT1, have been shown to be downregulated in Alzheimer's disease.[16] Potential therapeutic solutions to glucose transporter deficiency in conditions such as Alzheimer's include glucagon-like peptide 1 (GLP-1) analog treatment. Although GLP-1 agonists have been proven to increase insulin secretion by the pancreas in type II diabetes mellitus[17], it is unclear how they affect glucose transporter kinetics in the brain. Structural highlightsThe GLUT1 transporter has one known site at Asn 45. Varied molecular weights of the GLUT1 transporter suggest glycosylation is dependent on cell type. This glycosylation site is thought to be important for increasing glucose binding to the extracellular portion of the transporter. Mutations in the GLUT1 transporter from Asn 45 to an Asp, Tyr, or Gln residue have been shown to increase the Km of the enzyme.[18] In addition, samples of both bovine capillaries and choroid plexus cells show differences in GLUT1 molecular weight attributable to N-linked glycosylation.[19] This evidence suggests that GLUT1 glycosylation may differ by tissue type to serve certain functions. GLUT1 and Glut3 have a that are predicted to stabilize the "outward" conformation of both proteins, allowing extracellular glucose binding.[20] These motifs are referred to as the "A" and "SP" motifs. The implications of this finding are that these two motifs may play a key role in conformational changes involved in glucose import. The sequence of the A motif, from residue 84 to residue 93, is G-L-F-V-N-R-F-G-R-R. The sequence of the SP motif, from residue 208 to residue 212, is P-E-S-P-R. has a and is proposed to be comprised of . In the structure 4pyp, these residues are Gly27, Thr30, Ile164, Val165, Ile168, and Phe291. This hydrophobic pocket has been proposed to facilitate substrate binding and unbinding between the "occluded" and "inward-open" conformations.[21] In this crystal structure, acts as a glucose analog that binds the hydrophobic pocket.[22] The GLUT1 transporter also has three ATP-binding sites. The lone is proposed to be comprised of the residues Gly111, Phe112, Ser113, Lys114, Leu115, Gly116, Lys117, and Ser118. This is a domain consistent with Walker Motif A (G-X-X-G/X-X-G-K-T/X). The is one of two in the cytoplasmic portion of the protein. The residues comprising this ATP-binding site are Lys225, Ser226, Val227, Leu228, and Lys229. The , also localized to the cytoplasm, is comprised of the amino acids Gly332, Arg 333, Arg334, Thr335, Leu336, His337, and Leu338. This sequence is consistent with Walker Motif B (G-X-X-X-L-X-X).[23] As mentioned earlier in this page, both Walker motifs A and B are highly conserved. Some studies on GLUT1 show that ATP binding to the cytosolic domains causes C-terminus binding to the C-terminal side of the intracellular loop of the protein, preventing substrate import. ATP binding is not known to have any effects when binding extracellularly.[24] Several types of GLUT1 inhibitors exist, one being cytochalasin b. Two Trp residues, Trp388 and Trp412, are thought to play a major role in via hydrophobic interactions.[25] There is at least one known amino acid substitution in GLUT1 that can cause GLUT1 deficiency syndrome. causes transmembrane helix #4 to become kinked, blocking substrate transport. Arg126 is the amino acid most often mutated in GLUT1 deficiency syndrome.[26] GLUT1, and other glucose transporters, have an . The ICH domain of GLUT1 may play a role in stabilizing the outward-facing conformation of the enzyme based on computer modeling in MODELLER.[27] Two residues of interest in the ICH domain are Arg212 and Asp240. These residues are hypothesized to participate in hydrogen bonding between the ICH domain and transmembrane domains of the protein with the cumulative effect of stabilizing the outward-facing conformation. References
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