{"uniprot":"A6NN92","gene":"GJE1","name":"Putative gap junction epsilon-1 protein","organism":"Homo sapiens (Human)","status":"dark","length":205,"sequence":"MSLNYIKNFYEGCVKPPTVIGQFHTLFFGSIRIFFLGVLGFAVYGNEALHFICDPDKREVNLFCYNQFRPITPQVSFSALQLVIVLVPGALFHLYAACKSINQECILQKPIYTIIYILSVLLRISLAAIAFWLQIYLFGFQVKSLYLCDARSLGENMIIRCMVPEHFEKTIFLIAINTFTTITILLFVAEIFEIIFRRLYFPFRQ","function_summary":"A multi-pass membrane channel that assembles into hexameric hemichannels and docks across adjacent cells to form gap junctions. Its N-terminal gating modules and disulfide-stabilized extracellular loops create a low-resistance pore that equilibrates ions and small metabolites between neighboring cells, thereby mediating intercellular coupling and transport. The protein is synthesized and assembled within membrane-bounded organelles of the secretory pathway before concentrating at cell–cell contacts to form junctional plaques.","plain_language":"GJE1 has barely been studied. The model's best guess: A multi-pass membrane channel that assembles into hexameric hemichannels and docks across adjacent cells to form gap junctions. Its N-terminal gating modules and disulfide-stabilized extracellular loops create a low-resistance pore that equilibrates ions and small metabolites between neighboring cells, thereby mediating intercellular coupling and transport.","uniprot_summary":"One gap junction consists of a cluster of hemichannels through which substances of low MW diffuse from one cell to a neighboring cell.","go_terms":{"molecular_function":[{"id":"GO:0005243","label":"gap junction channel activity"}],"biological_process":[{"id":"GO:0055085","label":"transmembrane transport"}],"cellular_component":[{"id":"GO:0043231","label":"intracellular membrane-bounded organelle"}]},"interpro":[{"id":"IPR038359","name":"Connexin, N-terminal domain superfamily","type":"homologous_superfamily","start":1,"end":201},{"id":"IPR013092","name":"Connexin, N-terminal","type":"domain","start":5,"end":104},{"id":"IPR013092","name":"Connexin, N-terminal","type":"domain","start":113,"end":195},{"id":"IPR019570","name":"Connexin, cysteine-rich domain","type":"domain","start":126,"end":194},{"id":"IPR000500","name":"Connexin","type":"family","start":1,"end":104}],"reasoning":"I begin with the InterPro architecture. The sequence is dominated by connexin signatures: IPR038359 (Connexin, N-terminal domain superfamily, residues 1–201) blankets the full length, indicating a canonical connexin scaffold. Within this, two N-terminal connexin domains are detected—IPR013092 (Connexin, N-terminal, residues 5–104) followed by IPR013092 (Connexin, N-terminal, residues 113–195). This bipartite N-terminus is characteristic of connexins and forms the cytoplasmic gating and voltage-sensing apparatus that controls pore opening. The central extracellular architecture is reinforced by IPR019570 (Connexin, cysteine-rich domain, residues 126–194), which encodes the paired extracellular loops rich in conserved cysteines that form disulfide bonds. These disulfides rigidify the extracellular vestibule and enforce hemichannel docking specificity. Finally, IPR000500 (Connexin family, residues 1–104) anchors the protein within the connexin superfamily that assembles six transmembrane helices per connexon. The ordered layout—N-terminal gating modules leading into cysteine-stabilized extracellular loops—causes formation of a hexameric hemichannel that docks head-to-head with a partner hemichannel from an adjacent cell to create an intercellular aqueous conduit.\n\nThis architecture dictates the molecular function: a connexin hemichannel that, when docked, produces gap junction channel activity (GO:0005243). The N-terminal domains coordinate voltage and pH gating, while the cysteine-rich extracellular loops ensure precise intercellular docking and permeability to ions and small metabolites. Because these channels provide a low-resistance pathway across cell-cell interfaces, they directly mediate transmembrane transport (GO:0055085) in the specialized sense of coupling one membrane’s state to another.\n\nThe cellular context follows from assembly and trafficking. Connexins are synthesized and oligomerized in the endoplasmic reticulum and traverse the secretory pathway before reaching the plasma membrane at cell-cell contacts. This itinerary places the protein within intracellular membrane-bounded organelles (GO:0043231) during biogenesis and delivery, and ultimately at gap junction plaques at the cell surface. The multi-pass membrane nature inferred from the connexin family and the N-terminal gating modules aligns with a stable membrane-embedded state once assembled into junctional channels.\n\nMechanistically, the protein likely forms a hexameric hemichannel that gates via its N-terminal helices and undergoes extracellular disulfide-stabilized docking to generate a continuous intercellular pore. This pore equilibrates ions and small solutes between neighboring cells, coordinating electrical and metabolic coupling. I hypothesize that assembly and function depend on interactions with ER chaperones and junctional scaffolds: ER-resident lectins and quality-control factors guide folding and oligomerization; at the membrane, cytoskeletal and plaque-associated proteins stabilize channel clusters. Together, these interactions produce a regulated conduit that supports intercellular communication and homeostatic coupling.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A6NN92.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A6NN92"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A6NN92/entry","atlas":"/p/A6NN92"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}