{"uniprot":"A6NNM8","gene":"TTLL13P","name":"Tubulin polyglutamylase TTLL13P","organism":"Homo sapiens (Human)","status":"dark","length":815,"sequence":"MEPSTCRTMESEEDYVEEKESEKCVKEGVTNPSNSSQQALLKADYKALKNGVPSPIMATKIPKKVIAPVDTGDLEAGRRKRRRKRRSLAINLTNCKYESVRRAAQMCGLKEVGEDEEWTLYWTDCAVSLERVMDMKRFQKINHFPGMTEICRKDLLARNLNRMYKLYPSEYNIFPRTWCLPADYGDFQSYGRQRKARTYICKPDSGCQGRGIFITRNPREIKPGEHMICQQYISKPLLIDGFKFDMRVYVLITSCDPLRIFTYEEGLARFATTPYMEPSHNNLDNVCMHLTNYAINKHNENFVRDGAVGSKRKLSTLNIWLQEHSYNPGELWGDIEDIIIKTIISAHSVLRHNYRTCFPQYLNGGTCACFEILGFDILLDHKLKPWLLEVNHSPSFTTDSCLDQEVKDALLCDAMTLVNLRGCDKRKVMEEDKRRVKERLFQCYRQPRESRKEKTESSHVAMLDQERYEDSHLGKYRRIYPGPDTEKYARFFKHNGSLFQETAASKAREECARQQLEEIRLKQEQQETSGTKRQKARDQNQGESAGEKSRPRAGLQSLSTHLAYRNRNWEKELLPGQLDTMRPQEIVEEEELERMKALLQRETLIRSLGIVEQLTRLQHPGPQGQKKLHESRDRLGSQELKSMSLVLLVLLRGAATEQGAPHFLHPVLPHESIPRILGALPSMNAAIPHVPRYHLQPKNFNWTGEPAAINSCSLSMKKAGRCYFSSARIRLTSQGQASRRLEAINRVLAGSVPPTLTPKQGYFLQPERVASDSWTECTLPSMVNSEHRAAKVPLCPASAPMLQRSRALLNINQFR","function_summary":"A soluble cytosolic enzyme that installs glutamate side chains onto tubulin tails, thereby writing a polyglutamylation mark that tunes microtubule stability and the recruitment of associated proteins. By catalyzing ATP-dependent glutamyl addition to tubulin, it modulates cytoskeletal dynamics and contributes to orderly cell cycle transitions. Its soluble architecture supports cytosolic residency with transient engagement of microtubule-rich assemblies to coordinate post-translational control of the cytoskeleton.","plain_language":"TTLL13P has barely been studied. The model's best guess: A soluble cytosolic enzyme that installs glutamate side chains onto tubulin tails, thereby writing a polyglutamylation mark that tunes microtubule stability and the recruitment of associated proteins. By catalyzing ATP-dependent glutamyl addition to tubulin, it modulates cytoskeletal dynamics and contributes to orderly cell cycle transitions.","uniprot_summary":"Probable tubulin polyglutamylase that catalyzes the post-translational addition of glutamate residues to tubulin. May be involved in regulation of the cytoskeleton and in cell cycle progression.","go_terms":{"molecular_function":[{"id":"GO:0070740","label":"tubulin-glutamic acid ligase activity"}],"biological_process":[{"id":"GO:0018095","label":"protein polyglutamylation"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"}]},"interpro":[{"id":"IPR004344","name":"Tubulin-tyrosine ligase/Tubulin polyglutamylase","type":"family","start":85,"end":430}],"reasoning":"I begin with the domain architecture. The protein contains a single, centrally placed InterPro signature IPR004344 (Tubulin-tyrosine ligase/Tubulin polyglutamylase family) spanning residues 85–430. This family defines the TTL/TTLL enzyme superfamily that catalyzes ATP-dependent post-translational modifications on tubulin. The breadth of the IPR004344 coverage across the catalytic core indicates a soluble enzyme that binds ATP and glutamate to form isopeptide linkages on target proteins. The absence of transmembrane segments and the soluble enzyme fold argue for a cytosolic enzyme that transiently associates with cytoskeletal assemblies.\n\nThis TTL/TTLL core dictates the molecular function: it catalyzes ligation of glutamate onto tubulin tails, i.e., tubulin-glutamic acid ligase activity (GO:0070740). The chemistry of this family proceeds by activating glutamate and forming a γ-glutamyl isopeptide bond to the exposed C-terminal tails of tubulin, a reaction class that directly establishes and extends glutamyl side chains. That enzymatic role causally places the protein in the biological process of protein polyglutamylation (GO:0018095), because repeated addition of glutamate units modulates microtubule behavior and the recruitment of microtubule-associated proteins.\n\nFrom this enzymology and process, I infer cellular context. Enzymes of the TTL/TTLL family operate in the soluble phase of the cell and engage microtubules through transient binding; thus a cytosolic localization is expected and aligns with GO:0005829 cytosol. The soluble catalytic architecture and lack of targeting signals support a cytosolic pool that can shuttle to microtubule-rich regions when needed.\n\nMechanistically, the enzyme’s single TTL/TTLL catalytic module (residues 85–430) binds ATP and glutamate and recognizes acidic tubulin tails, installing glutamate units that tune microtubule dynamics and MAP/catastrophe-rescue factor binding. This modification pathway explains how the enzyme influences cytoskeletal regulation and cell cycle transitions: polyglutamylation modulates microtubule stability and trafficking, which feed forward into mitotic spindle function and checkpoint timing.\n\nGiven this mechanism, I hypothesize interaction partners that enable targeting and function. The primary substrates and transient cofactors are α/β-tubulin dimers and assembled microtubules. The enzyme likely forms transient complexes with tubulin-assembly factors and microtubule-associated proteins that read or compete for glutamyl marks. It may also coordinate with cytosolic chaperonins that maintain tubulin folding and with cell-cycle regulators that synchronize modification with mitosis. Together, these interactions position the enzyme as a cytosolic modifier that writes a glutamyl code on tubulin to orchestrate cytoskeletal behavior and cell cycle progression.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A6NNM8.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A6NNM8"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A6NNM8/entry","atlas":"/p/A6NNM8"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}