{"uniprot":"P11166","gene":"SLC2A1","name":"Solute carrier family 2, facilitated glucose transporter member 1 (GLUT1)","organism":"Homo sapiens (Human)","status":"known control","length":492,"sequence":"MEPSSKKLTGRLMLAVGGAVLGSLQFGYNTGVINAPQKVIEEFYNQTWVHRYGESILPTTLTTLWSLSVAIFSVGGMIGSFSVGLFVNRFGRRNSMLMMNLLAFVSAVLMGFSKLGKSFEMLILGRFIIGVYCGLTTGFVPMYVGEVSPTALRGALGTLHQLGIVVGILIAQVFGLDSIMGNKDLWPLLLSIIFIPALLQCIVLPFCPESPRFLLINRNEENRAKSVLKKLRGTADVTHDLQEMKEESRQMMREKKVTILELFRSPAYRQPILIAVVLQLSQQLSGINAVFYYSTSIFEKAGVQQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALALLEQLPWMSYLSIVAIFGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCFQYVEQLCGPYVFIIFTVLLVLFFIFTYFKVPETKGRTFDEIASGFRQGGASQSDKTPEELFHPLGADSQV","function_summary":"A multi-pass membrane uniporter that provides constitutive, high-affinity uptake of glucose and related hexoses, and also conducts L-ascorbate and select long-chain fatty acids. Its alternating-access pore supports basal sugar and vitamin flux across the plasma membrane and endothelial interfaces, sustaining carbohydrate and redox metabolism and contributing to neural energy supply and barrier transport. The transporter oligomerizes and associates with cortical actin and secretory pathways, explaining its polarized distribution at apical and basolateral surfaces, recycling through the Golgi, and occasional packaging into extracellular vesicles.","plain_language":"SLC2A1 is a well-known protein (transporter). What biology already knows: Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake. We use it to check whether the model gets it right.","uniprot_summary":"Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake.","go_terms":{"molecular_function":[{"id":"GO:0090482","label":"vitamin transmembrane transporter activity"},{"id":"GO:0005324","label":"long-chain fatty acid transporter activity"},{"id":"GO:0042802","label":"identical protein binding"},{"id":"GO:0043621","label":"protein self-association"},{"id":"GO:0015149","label":"hexose transmembrane transporter activity"},{"id":"GO:0005355","label":"glucose transmembrane transporter activity"},{"id":"GO:0055056","label":"D-glucose transmembrane transporter activity"}],"biological_process":[{"id":"GO:0005996","label":"monosaccharide metabolic process"},{"id":"GO:0005975","label":"carbohydrate metabolic process"},{"id":"GO:0034219","label":"carbohydrate transmembrane transport"},{"id":"GO:0098704","label":"carbohydrate import across plasma membrane"},{"id":"GO:0007417","label":"central nervous system development"},{"id":"GO:0019852","label":"L-ascorbic acid metabolic process"},{"id":"GO:0150104","label":"transport across blood-brain barrier"},{"id":"GO:0044539","label":"long-chain fatty acid import into cell"},{"id":"GO:1904659","label":"glucose transmembrane transport"}],"cellular_component":[{"id":"GO:0072562","label":"blood microparticle"},{"id":"GO:0030496","label":"midbody"},{"id":"GO:0045177","label":"apical part of cell"},{"id":"GO:0016324","label":"apical plasma membrane"},{"id":"GO:0070062","label":"extracellular exosome"},{"id":"GO:0016323","label":"basolateral plasma membrane"},{"id":"GO:0000139","label":"Golgi membrane"},{"id":"GO:0030864","label":"cortical actin cytoskeleton"}]},"interpro":[{"id":"IPR036259","name":"MFS transporter superfamily","type":"homologous_superfamily","start":1,"end":463},{"id":"IPR020846","name":"Major facilitator superfamily domain","type":"domain","start":15,"end":456},{"id":"IPR045263","name":"Glucose transporter GLUT","type":"family","start":5,"end":473},{"id":"IPR003663","name":"Sugar/inositol transporter","type":"family","start":19,"end":463},{"id":"IPR005828","name":"Major facilitator, sugar transporter-like","type":"family","start":19,"end":466},{"id":"IPR002439","name":"Glucose transporter, type 1 (GLUT1)","type":"family","start":42,"end":54},{"id":"IPR002439","name":"Glucose transporter, type 1 (GLUT1)","type":"family","start":467,"end":481},{"id":"IPR002439","name":"Glucose transporter, type 1 (GLUT1)","type":"family","start":483,"end":492},{"id":"IPR005829","name":"Sugar transporter, conserved site","type":"conserved_site","start":128,"end":153},{"id":"IPR005829","name":"Sugar transporter, conserved site","type":"conserved_site","start":324,"end":340}],"reasoning":"I begin with the InterPro architecture. The sequence is dominated by IPR036259 (MFS transporter superfamily, residues 1–463) and IPR020846 (Major facilitator superfamily domain, residues 15–456), establishing a canonical major facilitator superfamily fold that forms a 12-helix alternating-access pore across the membrane. Within this scaffold, three sugar-focused family signatures—IPR045263 (Glucose transporter GLUT family, residues 5–473), IPR003663 (Sugar/inositol transporter family, residues 19–463), and IPR005828 (Major facilitator, sugar transporter-like family, residues 19–466)—specify substrate preference for hexoses and related metabolites. Two GLUT1-specific family marks, IPR002439 (Glucose transporter, type 1 (GLUT1) family, residues 42–54), [467–481], and [483–492], anchor the identity of a high-affinity glucose transporter that also accommodates alternative substrates. Two conserved sequence elements—IPR005829 (Sugar transporter, conserved site, residues 128–153) and residues 324–340—map to pore-lining motifs that coordinate substrate and protonatable residues, enforcing an alternating-access mechanism. The ordered layout—MFS core spanning nearly the entire polypeptide, GLUT/GLUT1 family determinants, and conserved sugar-transporter motifs—causes a facilitative uniporter activity that translocates neutral sugars and certain acidic cofactors without direct coupling to ion gradients.\n\nFrom this architecture, the molecular function resolves as a multi-substrate facilitative transporter. The GLUT/GLUT1 signatures and conserved sugar-transporter sites drive GO:0055056 D-glucose transmembrane transporter activity and GO:0015149 hexose transmembrane transporter activity. The GLUT1 lineage is known to pass L-ascorbate; the same pore chemistry and binding cavity that stabilize glucose rationalize GO:0090482 vitamin transmembrane transporter activity and GO:0019852 L-ascorbic acid metabolic process at the systems level. The MFS fold also supports transport of long-chain fatty acids when the cavity accommodates amphipathic ligands; this explains GO:0005324 long-chain fatty acid transporter activity. The oligomeric behavior of MFS transporters—supported by broad family behavior and the need for cooperative gating—accounts for GO:0042802 identical protein binding and GO:0043621 protein self-association.\n\nThese molecular activities propagate to biological processes. Facilitated glucose flux directly instantiates GO:1904659 glucose transmembrane transport and GO:0098704 carbohydrate import across plasma membrane, feeding GO:0005975 carbohydrate metabolic process and GO:0005996 monosaccharide metabolic process. Transport of L-ascorbate through the same conduit supports GO:0019852 L-ascorbic acid metabolic process. The capacity to import long-chain fatty acids maps to GO:0044539 long-chain fatty acid import into cell. In specialized endothelia, this transporter’s high-capacity sugar/ascorbate flux across the vascular interface underlies GO:0150104 transport across blood-brain barrier, a prerequisite for neural energy supply and redox balance that contributes to GO:0007417 central nervous system development.\n\nCellular localization follows from the membrane-embedded MFS architecture and trafficking signals. The multi-pass topology and GLUT family signatures place the protein in the plasma membrane, with polarized epithelial distribution consistent with GO:0016324 apical plasma membrane and GO:0016323 basolateral plasma membrane. Its biosynthetic and recycling itinerary through the secretory pathway explains presence at GO:0000139 Golgi membrane. Association with cortical actin and membrane-cytoskeleton coupling supports GO:0030864 cortical actin cytoskeleton and transient enrichment at GO:0030496 midbody during cytokinesis. Packaging into extracellular vesicles and release from circulating cells rationalizes detection in GO:0070062 extracellular exosome and GO:0072562 blood microparticle.\n\nMechanistically, the transporter operates as a high-affinity facilitative uniporter that cycles between outward- and inward-facing states to equilibrate glucose, hexoses, and L-ascorbate across membranes; its amphipathic cavity can also accommodate long-chain fatty acids. Oligomerization stabilizes the transport core and tunes gating kinetics. In polarized cells and endothelial barriers, this mechanism sustains basal glucose uptake and neurovascular nutrient supply. I hypothesize that the transporter forms homo-oligomers and associates with cytoskeletal and trafficking hubs: at the cortex it likely binds actin-linked scaffolds to stabilize surface pools; in the Golgi it engages sorting machinery to maintain polarized distribution; and in vesicular pathways it transiently associates with exosome biogenesis modules. These assemblies would coordinate substrate flux with membrane domain identity and barrier function.","category":"control","control_evaluation":{"known_function":"Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake. Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses. Most important energy carrier of the brain: present at the blood-brain barrier and assures the energy-independent, facilitative transport of glucose into the brain. In association with BSG and NXNL1, promotes retinal cone survival by increasing glucose uptake into photoreceptors (By similarity). Required for mesendoderm differentiation (By similarity)","source":"UniProt P11166, GO annotations (all evidence for \"correct\"; experimental evidence for \"missed\", max 2 per aspect shown)","items":[{"aspect":"Molecular function","known":"dehydroascorbic acid transmembrane transporter activity · GO:0033300","predicted":"GO:0090482 vitamin transmembrane transporter activity","verdict":"correct"},{"aspect":"Molecular function","known":"long-chain fatty acid transmembrane transporter activity · GO:0005324","predicted":"GO:0005324 long-chain fatty acid transporter activity","verdict":"correct"},{"aspect":"Molecular function","known":"identical protein binding · GO:0042802","predicted":"GO:0042802 identical protein binding","verdict":"correct"},{"aspect":"Molecular function","known":"No annotation in UniProt","predicted":"GO:0043621 protein self-association","verdict":"speculative"},{"aspect":"Molecular function","known":"D-glucose transmembrane transporter activity · GO:0055056","predicted":"GO:0015149 hexose transmembrane transporter activity","verdict":"correct"},{"aspect":"Molecular function","known":"No annotation in UniProt","predicted":"GO:0005355 glucose transmembrane transporter activity","verdict":"speculative"},{"aspect":"Molecular function","known":"D-glucose transmembrane transporter activity · GO:0055056","predicted":"GO:0055056 D-glucose transmembrane transporter activity","verdict":"correct"},{"aspect":"Biological process","known":"L-ascorbic acid metabolic process · GO:0019852","predicted":"GO:0005996 monosaccharide metabolic process","verdict":"correct"},{"aspect":"Biological process","known":"L-ascorbic acid metabolic process · GO:0019852","predicted":"GO:0005975 carbohydrate metabolic process","verdict":"correct"},{"aspect":"Biological process","known":"D-glucose transmembrane transporter activity · GO:0055056","predicted":"GO:0034219 carbohydrate transmembrane transport","verdict":"correct"},{"aspect":"Biological process","known":"D-glucose import across plasma membrane · GO:0098708","predicted":"GO:0098704 carbohydrate import across plasma membrane","verdict":"correct"},{"aspect":"Biological process","known":"central nervous system development · GO:0007417","predicted":"GO:0007417 central nervous system development","verdict":"correct"},{"aspect":"Biological process","known":"L-ascorbic acid metabolic process · GO:0019852","predicted":"GO:0019852 L-ascorbic acid metabolic process","verdict":"correct"},{"aspect":"Biological process","known":"transport across blood-brain barrier · GO:0150104","predicted":"GO:0150104 transport across blood-brain barrier","verdict":"correct"},{"aspect":"Biological process","known":"long-chain fatty acid import across plasma membrane · GO:0015911","predicted":"GO:0044539 long-chain fatty acid import into cell","verdict":"correct"},{"aspect":"Biological process","known":"D-glucose transmembrane transport · GO:1904659","predicted":"GO:1904659 glucose transmembrane transport","verdict":"correct"},{"aspect":"Cellular component","known":"blood microparticle · GO:0072562","predicted":"GO:0072562 blood microparticle","verdict":"correct"},{"aspect":"Cellular component","known":"midbody · GO:0030496","predicted":"GO:0030496 midbody","verdict":"correct"},{"aspect":"Cellular component","known":"apical plasma membrane · GO:0016324","predicted":"GO:0045177 apical part of cell","verdict":"correct"},{"aspect":"Cellular component","known":"apical plasma membrane · GO:0016324","predicted":"GO:0016324 apical plasma membrane","verdict":"correct"},{"aspect":"Cellular component","known":"extracellular exosome · GO:0070062","predicted":"GO:0070062 extracellular exosome","verdict":"correct"},{"aspect":"Cellular component","known":"basolateral plasma membrane · GO:0016323","predicted":"GO:0016323 basolateral plasma membrane","verdict":"correct"},{"aspect":"Cellular component","known":"Golgi membrane · GO:0000139","predicted":"GO:0000139 Golgi membrane","verdict":"correct"},{"aspect":"Cellular component","known":"cortical actin cytoskeleton · GO:0030864","predicted":"GO:0030864 cortical actin cytoskeleton","verdict":"correct"},{"aspect":"Cellular component","known":"glucose transporter complex · GO:1990350","predicted":"—","verdict":"missed"},{"aspect":"Cellular component","known":"melanosome · GO:0042470","predicted":"—","verdict":"missed"},{"aspect":"Biological process","known":"photoreceptor cell maintenance · GO:0045494","predicted":"—","verdict":"missed"},{"aspect":"Biological process","known":"protein-containing complex assembly · GO:0065003","predicted":"—","verdict":"missed"}],"precision":0.917,"n_missed_exp":4,"n_known_exp":23},"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-P11166.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/P11166"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/P11166/entry","atlas":"/p/P11166"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}