{"uniprot":"Q96MI9","gene":"AGBL1","name":"Cytosolic carboxypeptidase 4","organism":"Homo sapiens (Human)","status":"dark","length":1112,"sequence":"MAEQEASGLQVLLHTLQSSSDKESILTILKVLGDLLSVGTDRRIHYMISKGGSEALLQTLVDTARTAPPDYDILLPLFRLLAKVGLRDKKIGRKALELEALDVTLILARKNLSHGQNLLHCLWALRVFASSVSMGAMLGINGAMELLFKVITPYTRKRTQAIRAATEVLAALLKSKSNGRRAVNRGYVTSLLGLHQDWHSHDTANAYVQIRRGLLLCLRHIAALRSGREAFLAAQGMEILFSTTQNCLDDKSMEPVISVVLQILRQCYPTSPLPLVTASSAYAFPVPGCITTEPPHDLPEEDFEDDGDDEVDKDSDTEDGKVEDDDLETDVNKLSSKPGLDRPEEELMQYEVMCLELSYSFEELQSKLGDDLNSEKTQYANHHHIPAAASSKQHCYSKDQSSCGQEREYAVQTSLLCRVKTGRSTVHLGSKKNPGVNLYQNVQSNSLRRDSSESEIPDIQASPKADAWDVDAIFCPRMSASFSNSTRTREVVKVIDKLLQTHLKRVPFHDPYLYMAKARRTSSVVDFKMMAFPDVWGHCPPPTTQPMLERKCGVQRIRIFEDIRRLIQPSDVINKVVFSLDEPWPLQDNASNCLRFFSKFESGNLRKAIQVREFEYDLLVNADVNSTQHQQWFYFKVSGMQAAIPYHFNIINCEKPNSQFNYGMQPTLYSVKEALLGKPTWIRTGHEICYYKNHYRQSTAVAGGASGKCYYTLTFAVTFPHSEDVCYLAYHYPYTYTALMTHLDILEKSVNLKEVYFRQDVLCQTLGGNPCPLVTITAMPESNSDEHLEQFRHRPYQVITARVHPGESNASWVMKGTLEFLVSSDPVARLLRENFIFKIIPMLNPDGVINGNHRCSLSGEDLNRQWLSPSAHLQPTIYHAKGLLYHLSSIGRSPVVFCDFHGHSQKKNVFLYGCSIKETLWQAACTVGTSTILEEVNYRTLPKILDKLAPAFTMSSCSFLVEKSRASTARVVVWREMGVSRSYTMESSYCGCNQGPYQCTQRLLERTKNERAHPVDGLQGLQFGTRELEEMGAMFCLGLLILELKSASCSHQLLAQAATLLSAEEDALDQHLQRLKSSNFLPKHIWFAYHFFAITNFFKMNLLLHVSPVCDT","function_summary":"A soluble human metalloexopeptidase that trims glutamate residues from the C-termini of modified proteins. It uses an N-terminal armadillo-repeat scaffold to assemble with substrates and cofactors and a C-terminal zinc-dependent catalytic core to hydrolyze terminal glutamates. By editing polyglutamylation on cytosolic targets—including tubulin—it fine-tunes post-translational modification states that influence cytoskeletal behavior and other intracellular pathways. The enzyme operates primarily in the cytoplasm with regulated nucleolar residency, where assembly factors and modified substrates concentrate.","plain_language":"AGBL1 has barely been studied. The model's best guess: A soluble human metalloexopeptidase that trims glutamate residues from the C-termini of modified proteins. It uses an N-terminal armadillo-repeat scaffold to assemble with substrates and cofactors and a C-terminal zinc-dependent catalytic core to hydrolyze terminal glutamates.","uniprot_summary":"Metalloprotease that mediates the proteolytic cleavage of a peptide or protein substrate at its carboxyl terminus.","go_terms":{"molecular_function":[{"id":"GO:0004181","label":"metallocarboxypeptidase activity"}],"biological_process":[{"id":"GO:0018410","label":"C-terminal protein amino acid modification"},{"id":"GO:0035609","label":"protein side chain glutamylation"}],"cellular_component":[{"id":"GO:0005737","label":"cytoplasm"},{"id":"GO:0005730","label":"nucleolus"}]},"interpro":[{"id":"IPR011989","name":"Armadillo-like helical","type":"homologous_superfamily","start":1,"end":266},{"id":"IPR016024","name":"Armadillo-type fold","type":"homologous_superfamily","start":8,"end":267},{"id":"IPR040626","name":"Cytosolic carboxypeptidase, N-terminal","type":"domain","start":597,"end":671},{"id":"IPR000834","name":"Peptidase M14, carboxypeptidase A","type":"domain","start":732,"end":1022},{"id":"IPR033852","name":"Cytosolic aminopeptidase 1/4","type":"domain","start":754,"end":1040},{"id":"IPR050821","name":"Cytosolic carboxypeptidase","type":"family","start":149,"end":1073}],"reasoning":"I begin with the InterPro architecture. The N-terminus (residues 1–266) carries two overlapping helical solenoid signatures: IPR011989 (Armadillo-like helical homologous_superfamily, residues 1–266) and IPR016024 (Armadillo-type fold homologous_superfamily, residues 8–267). Armadillo repeats form elongated, right-handed superhelices that create versatile protein–protein interaction scaffolds and often mediate subcellular targeting and assembly with regulatory partners. Midway through the sequence, a family-level envelope IPR050821 (Cytosolic carboxypeptidase family, residues 149–1073) spans from the Armadillo-rich N-terminus into the catalytic region, marking the protein as a cytosolic carboxypeptidase specialized for post-translational processing. Within the C-terminal half, IPR040626 (Cytosolic carboxypeptidase, N-terminal domain, residues 597–671) precedes the catalytic core and typically contributes to substrate positioning and metal coordination. The enzymatic heart is defined by IPR000834 (Peptidase M14, carboxypeptidase A domain, residues 732–1022), a zinc-dependent exopeptidase fold that removes residues from peptide/protein C-termini. Overlapping with this region, IPR033852 (Cytosolic aminopeptidase 1/4 domain, residues 754–1040) indicates a broader metallopeptidase scaffold that stabilizes the active site and supports exopeptidase chemistry. The ordered layout—N-terminal Armadillo scaffold for assembly and targeting, followed by a CCP-specific N-terminal module and a C-terminal M14 catalytic core—causally establishes a soluble, metal-dependent carboxypeptidase.\n\nThis architecture dictates molecular function. The M14 carboxypeptidase domain (IPR000834) and the CCP-specific modules (IPR040626, IPR050821) together create a metallocarboxypeptidase active site that hydrolyzes peptide bonds at the C-terminus of substrates. This directly supports GO:0004181 metallocarboxypeptidase activity. The Armadillo N-terminus explains how the enzyme assembles with substrates and cofactors and biases specificity toward polyglutamylated tails.\n\nFrom function to process, the catalytic preference for acidic C-termini and the CCP family identity explain participation in terminal protein modifications. The enzyme trims glutamate residues appended to protein C-termini, thereby executing GO:0018410 C-terminal protein amino acid modification. Its demonstrated role in editing polyglutamylation of tubulin fits GO:0035609 protein side chain glutamylation, where carboxypeptidase activity counterbalances elongation by removing glutamate units to tune post-translational marks.\n\nCellular location follows from both targeting and substrate ecology. The absence of transmembrane segments and the presence of Armadillo scaffolds favor a soluble intracellular enzyme, aligning with GO:0005737 cytoplasm. The nucleolus (GO:0005730 nucleolus) is a plausible second site because nucleoli concentrate RNA processing and specific protein assemblies; CCP-family scaffolds and Armadillo repeats can mediate transient nucleolar residency where polyglutamylation-sensitive substrates or assembly factors reside. Thus, a cytoplasmic enzyme with regulated nucleolar enrichment is expected.\n\nMechanistically, the N-terminal Armadillo platform recruits substrates and adaptors, the CCP-specific N-terminal domain orients the polyglutamylated tail, and the M14 catalytic core—stabilized by the overlapping metallopeptidase scaffold—coordinates a catalytic metal to hydrolyze terminal glutamates. This causes precise trimming of polyglutamylated proteins such as tubulin, thereby tuning microtubule dynamics and other cytoskeleton-dependent pathways.\n\nGiven this model, likely interaction partners include polyglutamylated substrates and their assembly machinery. Tubulin heterodimers and microtubule-associated proteins are prime binding/catalytic clients. TTLL family polyglutamylases are functional counterparts whose products CCP edits; transient complexes with these enzymes would channel substrates. Cytosolic chaperones and nucleolar assembly factors may stabilize targeting. Together, these interactions position the enzyme as a soluble editing carboxypeptidase that sculpts post-translational polyglutamylation landscapes in the cytoplasm and nucleolus.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q96MI9.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q96MI9"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q96MI9/entry","atlas":"/p/Q96MI9"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}