{"uniprot":"C9J202","gene":"ALG1L2","name":"Putative glycosyltransferase ALG1L2","organism":"Homo sapiens (Human)","status":"dark","length":215,"sequence":"MGATAGWAVTVYDKPASFFKEAPLDLQHRLFMKLGSTHSPFRARSEPEDPDTERSAFTERDSGSGLVTRLHERPALLVSSTSWTEFEQLTLDGQNLPSLVCVITGKGPLREYYSRLIHQKHFQHIQVCIPWLEGRGLPPLLGSVDLDVCLDTSSSGLDLPMKVVDMFRCCLPACAVNFKCLHELVKHEENRLVFEDSEELAAQLQYFADAFLKLS","function_summary":"A single-pass endoplasmic reticulum membrane enzyme that projects a soluble catalytic domain into the cytosol to initiate assembly of the lipid-linked oligosaccharide used for asparagine-linked protein glycosylation. It transfers N-acetylglucosamine from a nucleotide-sugar donor onto a dolichyl pyrophosphate–anchored chitobiose acceptor, thereby priming the pathway that builds the precursor for N-glycosylation. Anchoring at the ER concentrates cytosolic substrates and assembly partners, enabling efficient handoff of lipid-linked intermediates during early steps of glycan biosynthesis.","plain_language":"ALG1L2 has barely been studied. The model's best guess: A single-pass endoplasmic reticulum membrane enzyme that projects a soluble catalytic domain into the cytosol to initiate assembly of the lipid-linked oligosaccharide used for asparagine-linked protein glycosylation. It transfers N-acetylglucosamine from a nucleotide-sugar donor onto a dolichyl pyrophosphate–anchored chitobiose acceptor, thereby priming the pathway that builds the precursor for N-glycosylation.","uniprot_summary":"Involved in protein N-glycosylation pathway. Catalyzes the initial step in assembly of lipid-linked oligosaccharide precursor for N-glycosylation.","go_terms":{"molecular_function":[{"id":"GO:0008375","label":"acetylglucosaminyltransferase activity"},{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0018279","label":"protein N-linked glycosylation via asparagine"}],"cellular_component":[{"id":"GO:0005789","label":"endoplasmic reticulum membrane"},{"id":"GO:0005829","label":"cytosol"}]},"interpro":[{"id":"IPR001296","name":"Glycosyl transferase, family 1","type":"domain","start":94,"end":207},{"id":"IPR026051","name":"Chitobiosyldiphosphodolichol beta-mannosyltransferase ALG1-like","type":"family","start":8,"end":209}],"reasoning":"I begin with the InterPro architecture. The polypeptide carries IPR026051 (Chitobiosyldiphosphodolichol beta-mannosyltransferase ALG1-like family) spanning residues 8–209, which envelops a catalytic core annotated as IPR001296 (Glycosyl transferase, family 1 domain) from residues 94–207. This arrangement—an ALG1-like family envelope that houses a GT1-type glycosyltransferase core—defines a soluble catalytic module that transfers N-acetylglucosamine from a nucleotide-sugar donor to a lipid-linked acceptor. The N-terminal stretch preceding residue 8 is short, consistent with a single transmembrane anchor that tethers an otherwise cytosolic catalytic domain to the endoplasmic reticulum membrane.\n\nThis domain architecture causes a specific molecular function. The GT1 catalytic core (IPR001296) confers glycosyltransferase chemistry, and the ALG1-like family (IPR026051) specifies the reaction as the initial beta-mannosyl addition step in lipid-linked oligosaccharide assembly. Together, these features necessitate GO:0008375 acetylglucosaminyltransferase activity: the enzyme uses UDP-GlcNAc to elaborate the chitobiose pyrophosphate dolichol precursor. The presence of a membrane anchor with a soluble catalytic head predicts extensive macromolecular contacts—both membrane-protein scaffolding and soluble complex assembly—supporting GO:0005515 protein binding as an intrinsic property of this assembly-line enzyme.\n\nFrom this chemistry, the biological process follows. By installing the first beta-linked mannose onto dolichyl pyrophosphate–anchored chitobiose, the enzyme commits the pathway that builds the lipid-linked oligosaccharide precursor for asparagine-linked glycosylation. This causally places the protein in GO:0018279 protein N-linked glycosylation via asparagine, upstream of oligosaccharide transfer to nascent polypeptides.\n\nCellular location is dictated by the anchor and pathway topology. A single-pass membrane segment positions the catalytic GT1 module on the cytosolic face of the endoplasmic reticulum, aligning with GO:0005789 endoplasmic reticulum membrane. The soluble catalytic head projects into the cytosol, consistent with GO:0005829 cytosol, where nucleotide-sugar pools and cytosolic lipid-binding factors are accessible. This topology explains how the enzyme samples cytosolic UDP-GlcNAc while remaining membrane-tethered for substrate channeling.\n\nMechanistically, the single-pass ER membrane anchor recruits and stabilizes a glycosylation assembly line. The ALG1-like envelope and GT1 core cooperate to bind UDP-GlcNAc and the dolichyl-PP-linked chitobiose acceptor, catalyzing transfer and releasing UDP. The membrane tether concentrates the enzyme with upstream and downstream partners to ensure efficient handoff of the lipid-linked intermediate. I hypothesize that it forms transient complexes with other early-acting N-glycosylation enzymes and accessory factors—such as ALG2 and ALG12 that remodel and extend the lipid-linked oligosaccharide, as well as soluble UDP-sugar handling proteins—to coordinate substrate flow from cytosol to ER membrane and onward to oligosaccharyltransferase.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-C9J202.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/C9J202"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/C9J202/entry","atlas":"/p/C9J202"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}