{"uniprot":"P07550","gene":"ADRB2","name":"Beta-2 adrenergic receptor","organism":"Homo sapiens (Human)","status":"known control","length":413,"sequence":"MGQPGNGSAFLLAPNGSHAPDHDVTQERDEVWVVGMGIVMSLIVLAIVFGNVLVITAIAKFERLQTVTNYFITSLACADLVMGLAVVPFGAAHILMKMWTFGNFWCEFWTSIDVLCVTASIETLCVIAVDRYFAITSPFKYQSLLTKNKARVIILMVWIVSGLTSFLPIQMHWYRATHQEAINCYANETCCDFFTNQAYAIASSIVSFYVPLVIMVFVYSRVFQEAKRQLQKIDKSEGRFHVQNLSQVEQDGRTGHGLRRSSKFCLKEHKALKTLGIIMGTFTLCWLPFFIVNIVHVIQDNLIRKEVYILLNWIGYVNSGFNPLIYCRSPDFRIAFQELLCLRRSSLKAYGNGYSSNGNTGEQSGYHVEQEKENKLLCEDLPGTEDFVGHQGTVPSDNIDSQGRNCSTNDSLL","function_summary":"A seven-transmembrane adrenergic receptor that senses catecholamines at the cell surface and activates G protein signaling to elevate cAMP, stimulate PKA and MAPK pathways, and modulate downstream targets including potassium channels and synaptic receptor systems. It assembles into higher-order complexes and homodimers, undergoes regulated endocytosis, and traffics through endosomes to lysosomes after internalization. The receptor’s architecture and trafficking motifs coordinate robust signaling at the plasma membrane and through the Golgi–endosome–lysosome route, integrating stress responses and amyloid-beta engagement with canonical adrenergic signaling.","plain_language":"ADRB2 is a well-known protein (GPCR). What biology already knows: G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, activating bifurcated signaling pathways. We use it to check whether the model gets it right.","uniprot_summary":"Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins.","go_terms":{"molecular_function":[{"id":"GO:0044877","label":"protein-containing complex binding"},{"id":"GO:0042277","label":"peptide binding"},{"id":"GO:0015459","label":"potassium channel regulator activity"},{"id":"GO:0042803","label":"protein homodimerization activity"},{"id":"GO:0001540","label":"amyloid-beta binding"},{"id":"GO:0004935","label":"adrenergic receptor activity"}],"biological_process":[{"id":"GO:0006950","label":"response to stress"},{"id":"GO:0007166","label":"cell surface receptor signaling pathway"},{"id":"GO:0071875","label":"adrenergic receptor signaling pathway"},{"id":"GO:0045744","label":"negative regulation of G protein-coupled receptor signaling pathway"},{"id":"GO:0010508","label":"positive regulation of autophagy"},{"id":"GO:0007188","label":"adenylate cyclase-modulating G protein-coupled receptor signaling pathway"},{"id":"GO:2000273","label":"positive regulation of signaling receptor activity"},{"id":"GO:0043243","label":"positive regulation of protein-containing complex disassembly"},{"id":"GO:0065003","label":"protein-containing complex assembly"},{"id":"GO:0010738","label":"regulation of protein kinase A signaling"},{"id":"GO:0008333","label":"endosome to lysosome transport"},{"id":"GO:0007169","label":"transmembrane receptor protein tyrosine kinase signaling pathway"},{"id":"GO:0043410","label":"positive regulation of MAPK cascade"},{"id":"GO:2000311","label":"regulation of AMPA receptor activity"},{"id":"GO:1901098","label":"positive regulation of autophagosome maturation"},{"id":"GO:0002029","label":"desensitization of G protein-coupled receptor signaling pathway"},{"id":"GO:0032091","label":"negative regulation of protein binding"},{"id":"GO:1904646","label":"cellular response to amyloid-beta"},{"id":"GO:0006898","label":"receptor-mediated endocytosis"},{"id":"GO:0007190","label":"activation of adenylate cyclase activity"},{"id":"GO:1901653","label":"cellular response to peptide"},{"id":"GO:2000479","label":"regulation of cAMP-dependent protein kinase activity"}],"cellular_component":[{"id":"GO:0043235","label":"receptor complex"},{"id":"GO:0005794","label":"Golgi apparatus"},{"id":"GO:0005886","label":"plasma membrane"},{"id":"GO:0010008","label":"endosome membrane"},{"id":"GO:0005764","label":"lysosome"},{"id":"GO:0030669","label":"clathrin-coated endocytic vesicle membrane"}]},"interpro":[{"id":"IPR017452","name":"GPCR, rhodopsin-like, 7TM","type":"domain","start":50,"end":326},{"id":"IPR000332","name":"Beta 2 adrenoceptor","type":"family","start":10,"end":30},{"id":"IPR000332","name":"Beta 2 adrenoceptor","type":"family","start":34,"end":336},{"id":"IPR000276","name":"G protein-coupled receptor, rhodopsin-like","type":"family","start":35,"end":340},{"id":"IPR002233","name":"Adrenoceptor family","type":"family","start":88,"end":99},{"id":"IPR002233","name":"Adrenoceptor family","type":"family","start":141,"end":149},{"id":"IPR002233","name":"Adrenoceptor family","type":"family","start":219,"end":226},{"id":"IPR002233","name":"Adrenoceptor family","type":"family","start":331,"end":340},{"id":"IPR000332","name":"Beta 2 adrenoceptor","type":"family","start":342,"end":360},{"id":"IPR000332","name":"Beta 2 adrenoceptor","type":"family","start":361,"end":380},{"id":"IPR000332","name":"Beta 2 adrenoceptor","type":"family","start":387,"end":406}],"reasoning":"I begin with the InterPro architecture. The core transmembrane engine is IPR017452 (GPCR, rhodopsin-like, 7TM domain, residues 50–326), which establishes a seven-helix bundle that transduces extracellular ligand binding into intracellular G protein coupling. This rhodopsin-like scaffold is reinforced by multiple family-level signatures that specify adrenergic identity and subtype: IPR000332 (Beta 2 adrenoceptor family, residues 10–30; 34–336) and IPR000276 (G protein-coupled receptor, rhodopsin-like family, residues 35–340) together define a class A GPCR tuned for catecholamine sensing. Three adrenoceptor-family marks (IPR002233, residues 88–99; 141–149; 219–226; and a C-terminal adrenoceptor family mark at residues 331–340) map to conserved extracellular and intracellular loops that stabilize agonist binding and G protein engagement. The N- and C-terminal adrenoceptor family signatures (IPR000332 beta-2 adrenoceptor family, residues 342–360, 361–380, 387–406) bracket the cytoplasmic tail that recruits arrestins and endocytic machinery. This ordered layout—extracellular adrenoceptor determinants feeding a rhodopsin-like 7TM core and terminating in a regulatory cytoplasmic tail—causes catecholamine-triggered G protein signaling and receptor trafficking.\n\nFrom this architecture, the molecular function resolves as follows. The rhodopsin-like 7TM core and adrenoceptor determinants specify GO:0004935 adrenergic receptor activity and GO:0042277 peptide binding in the sense of catecholamine/peptidergic ligand recognition. The obligate coupling to heterotrimeric G proteins and assembly into higher-order receptor assemblies supports GO:0044877 protein-containing complex binding and GO:0042803 protein homodimerization activity; class A GPCRs often homodimerize and scaffold with cytosolic partners. The cytoplasmic tail and downstream cAMP/PKA signaling provide a mechanistic basis for GO:0015459 potassium channel regulator activity, as cAMP/PKA pathways modulate K+ channels via direct channel or adaptor interactions. The extracellular and luminal surfaces of this receptor can also capture amyloidogenic peptides, consistent with GO:0001540 amyloid-beta binding.\n\nThe biological process landscape follows directly from Gs-coupled cAMP signaling and regulated trafficking. The primary pathway is GO:0071875 adrenergic receptor signaling pathway and GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway, with GO:0007190 activation of adenylate cyclase activity and GO:2000479 regulation of cAMP-dependent protein kinase activity driving GO:0010738 regulation of protein kinase A signaling. These cascades propagate to GO:0043410 positive regulation of MAPK cascade and GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway via cAMP-sensitive nodes. The receptor’s endocytic itinerary—GO:0006898 receptor-mediated endocytosis, GO:0008333 endosome to lysosome transport, and GO:1901098 positive regulation of autophagosome maturation—arises from arrestin-mediated sorting and lysosomal delivery. Its influence on synaptic receptor systems is captured by GO:2000273 positive regulation of signaling receptor activity and GO:2000311 regulation of AMPA receptor activity, while stress and stress-hormone responses are reflected in GO:0006950 response to stress and GO:1904646 cellular response to amyloid-beta. The pathway can attenuate via GO:0002029 desensitization of G protein-coupled receptor signaling pathway and GO:0032091 negative regulation of protein binding through arrestin and coreceptor assemblies.\n\nCellular localization is dictated by the 7TM architecture and trafficking motifs. The receptor resides at the GO:0005886 plasma membrane and assembles into a GO:0043235 receptor complex. Biosynthetic and post-Golgi routing place it through the GO:0005794 Golgi apparatus. Agonist-induced internalization and sorting place it on the GO:0010008 endosome membrane and within GO:0030669 clathrin-coated endocytic vesicle membrane, with terminal delivery to the GO:0005764 lysosome.\n\nMechanistically, agonist binding stabilizes an active 7TM conformation that couples to Gs to elevate cAMP and activate PKA and MAPK pathways, while homodimerization and complex binding tune signal amplitude and duration. I hypothesize interactions with GNAS (Gs alpha), Gβγ subunits, adenylyl cyclases, GRKs, and beta-arrestins that drive endocytosis and lysosomal routing. Additional partners likely include amyloid-beta and amyloid-binding adaptors, K+ channel complexes regulated by cAMP/PKA, and synaptic receptor assemblies that coordinate AMPA receptor function. This ensemble explains catecholamine sensing, potassium channel regulation, amyloid-beta engagement, and the full spectrum of endocytic and signaling outcomes.","category":"control","control_evaluation":{"known_function":"G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, activating bifurcated signaling pathways. ADRB2 binds epinephrine (Epi) with an approximately 30-fold greater affinity than norepinephrine (NE). In the heart, Epi- and NE-activated ADRB2 induces rapid and slow cardiomyocyte contraction rate, respectively (By similarity). Both NE and Epi promote coupling to G(s)/PKA pathway to regulate myocyte contraction rate (By similarity). Epi also promotes ADRB2 coupling to G(i) proteins to exert cardioprotective effects especially in the conditions of hypoxia and oxidative stress through the G(i)/PI3K/Akt signaling pathway (By similarity). ADRB2-G(s) signaling delivers proapoptotic signals in cardiomyocytes although G(i)-mediated survival effect appears to predominate (By similarity). ADRB2 also transduces signals independently of PKA to regulate cellular pH by modulating Na(+)/H(+) exchanger SLC9A3 function","source":"UniProt P07550, GO annotations (all evidence for \"correct\"; experimental evidence for \"missed\", max 2 per aspect shown)","items":[{"aspect":"Molecular function","known":"protein-containing complex binding · GO:0044877","predicted":"GO:0044877 protein-containing complex binding","verdict":"correct"},{"aspect":"Molecular function","known":"amyloid-beta binding · GO:0001540","predicted":"GO:0042277 peptide binding","verdict":"correct"},{"aspect":"Molecular function","known":"potassium channel regulator activity · GO:0015459","predicted":"GO:0015459 potassium channel regulator activity","verdict":"correct"},{"aspect":"Molecular function","known":"protein homodimerization activity · GO:0042803","predicted":"GO:0042803 protein homodimerization activity","verdict":"correct"},{"aspect":"Molecular function","known":"amyloid-beta binding · GO:0001540","predicted":"GO:0001540 amyloid-beta binding","verdict":"correct"},{"aspect":"Molecular function","known":"beta2-adrenergic receptor activity · GO:0004941","predicted":"GO:0004935 adrenergic receptor activity","verdict":"correct"},{"aspect":"Biological process","known":"response to psychosocial stress · GO:1990911","predicted":"GO:0006950 response to stress","verdict":"correct"},{"aspect":"Biological process","known":"cell surface receptor signaling pathway · GO:0007166","predicted":"GO:0007166 cell surface receptor signaling pathway","verdict":"correct"},{"aspect":"Biological process","known":"adrenergic receptor signaling pathway · GO:0071875","predicted":"GO:0071875 adrenergic receptor signaling pathway","verdict":"correct"},{"aspect":"Biological process","known":"negative regulation of G protein-coupled receptor signaling pathway · GO:0045744","predicted":"GO:0045744 negative regulation of G protein-coupled receptor signaling pathway","verdict":"correct"},{"aspect":"Biological process","known":"positive regulation of autophagosome maturation · GO:1901098","predicted":"GO:0010508 positive regulation of autophagy","verdict":"correct"},{"aspect":"Biological process","known":"adenylate cyclase-modulating G protein-coupled receptor signaling pathway · GO:0007188","predicted":"GO:0007188 adenylate cyclase-modulating G protein-coupled receptor signaling pathway","verdict":"correct"},{"aspect":"Biological process","known":"No annotation in UniProt","predicted":"GO:2000273 positive regulation of signaling receptor activity","verdict":"speculative"},{"aspect":"Biological process","known":"positive regulation of autophagosome maturation · GO:1901098","predicted":"GO:0043243 positive regulation of protein-containing complex disassembly","verdict":"correct"},{"aspect":"Biological process","known":"No annotation in UniProt","predicted":"GO:0065003 protein-containing complex assembly","verdict":"speculative"},{"aspect":"Biological process","known":"No annotation in UniProt","predicted":"GO:0010738 regulation of protein kinase A signaling","verdict":"speculative"},{"aspect":"Biological process","known":"endosome to lysosome transport · GO:0008333","predicted":"GO:0008333 endosome to lysosome transport","verdict":"correct"},{"aspect":"Biological process","known":"cell surface receptor signaling pathway · GO:0007166","predicted":"GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway","verdict":"correct"},{"aspect":"Biological process","known":"positive regulation of MAPK cascade · GO:0043410","predicted":"GO:0043410 positive regulation of MAPK cascade","verdict":"correct"},{"aspect":"Biological process","known":"No annotation in UniProt","predicted":"GO:2000311 regulation of AMPA receptor activity","verdict":"speculative"},{"aspect":"Biological process","known":"positive regulation of autophagosome maturation · GO:1901098","predicted":"GO:1901098 positive regulation of autophagosome maturation","verdict":"correct"},{"aspect":"Biological process","known":"negative regulation of G protein-coupled receptor signaling pathway · GO:0045744","predicted":"GO:0002029 desensitization of G protein-coupled receptor signaling pathway","verdict":"correct"},{"aspect":"Biological process","known":"No annotation in UniProt","predicted":"GO:0032091 negative regulation of protein binding","verdict":"speculative"},{"aspect":"Biological process","known":"cellular response to amyloid-beta · GO:1904646","predicted":"GO:1904646 cellular response to amyloid-beta","verdict":"correct"},{"aspect":"Biological process","known":"receptor-mediated endocytosis · GO:0006898","predicted":"GO:0006898 receptor-mediated endocytosis","verdict":"correct"},{"aspect":"Biological process","known":"No annotation in UniProt","predicted":"GO:0007190 activation of adenylate cyclase activity","verdict":"speculative"},{"aspect":"Biological process","known":"No annotation in UniProt","predicted":"GO:1901653 cellular response to peptide","verdict":"speculative"},{"aspect":"Biological process","known":"No annotation in UniProt","predicted":"GO:2000479 regulation of cAMP-dependent protein kinase activity","verdict":"speculative"},{"aspect":"Cellular component","known":"signaling receptor complex · GO:0043235","predicted":"GO:0043235 receptor complex","verdict":"correct"},{"aspect":"Cellular component","known":"Golgi apparatus · GO:0005794","predicted":"GO:0005794 Golgi apparatus","verdict":"correct"},{"aspect":"Cellular component","known":"plasma membrane · GO:0005886","predicted":"GO:0005886 plasma membrane","verdict":"correct"},{"aspect":"Cellular component","known":"endosome membrane · GO:0010008","predicted":"GO:0010008 endosome membrane","verdict":"correct"},{"aspect":"Cellular component","known":"lysosome · GO:0005764","predicted":"GO:0005764 lysosome","verdict":"correct"},{"aspect":"Cellular component","known":"clathrin-coated endocytic vesicle membrane · GO:0030669","predicted":"GO:0030669 clathrin-coated endocytic vesicle membrane","verdict":"correct"},{"aspect":"Molecular function","known":"norepinephrine binding · GO:0051380","predicted":"—","verdict":"missed"},{"aspect":"Biological process","known":"positive regulation of glutamate receptor signaling pathway · GO:1900451","predicted":"—","verdict":"missed"}],"precision":0.765,"n_missed_exp":2,"n_known_exp":28},"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-P07550.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/P07550"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/P07550/entry","atlas":"/p/P07550"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}