{"uniprot":"Q8N4N3","gene":"KLHL36","name":"Kelch-like protein 36","organism":"Homo sapiens (Human)","status":"dark","length":616,"sequence":"MMEGSRQTRVSRPYKISESSKVYRWADHSSTVLQRLNEQRLRGLFCDVVLVADEQRVPAHRNLLAVCSDYFNSMFTIGMREAFQKEVELIGASYIGLKAVVDFLYGGELVLDGGNIDYVLETAHLLQIWTVVDFCCEYLEQEVSEDNYLYLQELASIYSLKRLDAFIDGFILNHFGTLSFTPDFLQNVSMQKLCVYLSSSEVQRECEHDLLQAALQWLTQQPEREAHARQVLENIHFPLIPKNDLLHRVKPAVCSLLPKEANCEGFIEEAVRYHNNLAAQPVMQTKRTALRTNQERLLFVGGEVSERCLELSDDTCYLDAKSEQWVKETPLPARRSHHCVAVLGGFIFIAGGSFSRDNGGDAASNLLYRYDPRCKQWIKVASMNQRRVDFYLASIEDMLVAIGGRNENGALSSVETYSPKTDSWSYVAGLPRFTYGHAGTIYKDFVYISGGHDYQIGPYRKNLLCYDHRTDVWEERRPMTTARGWHSMCSLGDSIYSIGGSDDNIESMERFDVLGVEAYSPQCNQWTRVAPLLHANSESGVAVWEGRIYILGGYSWENTAFSKTVQVYDREADKWSRGVDLPKAIAGGSACVCALEPRPEDKKKKGKGKRHQDRGQ","function_summary":"A cytosolic adaptor that assembles a cullin-based ubiquitin ligase to control substrate selection and turnover. Its N-terminal assembly module recruits the cullin scaffold, while a C-terminal beta-propeller recognizes specific targets, including cytoskeletal and Rac-pathway regulators. By positioning substrates for K48-linked polyubiquitination, it drives proteasome-dependent degradation that tunes cytoskeletal dynamics and signaling, with enrichment at the midbody during cytokinesis and residence within cullin–RING ligase assemblies.","plain_language":"KLHL36 has barely been studied. The model's best guess: A cytosolic adaptor that assembles a cullin-based ubiquitin ligase to control substrate selection and turnover. Its N-terminal assembly module recruits the cullin scaffold, while a C-terminal beta-propeller recognizes specific targets, including cytoskeletal and Rac-pathway regulators.","uniprot_summary":"May function as a substrate-specific adapter of an E3 ubiquitin-protein ligase complex.","go_terms":{"molecular_function":[{"id":"GO:0097602","label":"cullin family protein binding"}],"biological_process":[{"id":"GO:0043161","label":"proteasome-mediated ubiquitin-dependent protein catabolic process"},{"id":"GO:0035020","label":"regulation of Rac protein signal transduction"},{"id":"GO:0070936","label":"protein K48-linked ubiquitination"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0030496","label":"midbody"},{"id":"GO:0031463","label":"Cul3-RING ubiquitin ligase complex"}]},"interpro":[{"id":"IPR011333","name":"SKP1/BTB/POZ domain superfamily","type":"homologous_superfamily","start":21,"end":169},{"id":"IPR015915","name":"Kelch-type beta-propeller","type":"homologous_superfamily","start":280,"end":605},{"id":"IPR000210","name":"BTB/POZ domain","type":"domain","start":36,"end":143},{"id":"IPR011705","name":"BTB/Kelch-associated","type":"domain","start":148,"end":250},{"id":"IPR017096","name":"BTB-kelch protein","type":"family","start":6,"end":593},{"id":"IPR006652","name":"Kelch repeat type 1","type":"repeat","start":296,"end":444},{"id":"IPR006652","name":"Kelch repeat type 1","type":"repeat","start":445,"end":493},{"id":"IPR006652","name":"Kelch repeat type 1","type":"repeat","start":494,"end":546},{"id":"IPR006652","name":"Kelch repeat type 1","type":"repeat","start":547,"end":595}],"reasoning":"I begin with the domain architecture. The N-terminus carries IPR011333 (SKP1/BTB/POZ domain superfamily, residues 21–169) and a more specific IPR000210 (BTB/POZ domain, residues 36–143). BTB/POZ modules nucleate higher-order assemblies and, in BTB–Kelch proteins, create the docking surface for cullin scaffolds—most notably CUL3—thereby establishing a cullin–RING ligase platform. Immediately C-terminal to the BTB core lies IPR011705 (BTB/Kelch-associated, residues 148–250), a linker that stabilizes the BTB fold and couples it to the substrate-recognition module. The C-terminal half is a canonical Kelch β-propeller defined by IPR015915 (Kelch-type beta-propeller superfamily, residues 280–605) and reinforced by multiple IPR006652 Kelch repeat type-1 units spanning residues 296–444, 445–493, 494–546, and 547–595. This β-propeller architecture forms a rigid, radially arranged substrate-binding surface that selects target proteins. The overall composition is captured by IPR017096 (BTB-kelch protein family, residues 6–593), which unifies the N-terminal BTB assembly domain and the C-terminal Kelch recognition platform into a single adaptor framework.\n\nThis ordered BTB-to-Kelch layout dictates molecular function. The BTB/POZ domain and its associated region create the high-affinity interface for cullin scaffolds, directly supporting GO:0097602 cullin family protein binding. The Kelch β-propeller then confers substrate specificity, positioning targets for ubiquitin transfer by the CUL3–RING catalytic core. Together, this architecture causes assembly of a CUL3-based ubiquitin ligase that modifies bound substrates.\n\nFrom this molecular function, the biological processes follow. By recruiting substrates to a CUL3–RING ligase, the complex catalyzes GO:0070936 protein K48-linked ubiquitination, a linkage that commits targets to GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process. One substrate class comprises cytoskeletal regulators: the Kelch propeller is well-suited to recognize actin- and membrane-associated proteins, enabling controlled turnover that tunes cell morphology and division. A second substrate class centers on small GTPase pathways; by steering ubiquitination of pathway components that modulate Rac signaling, the adaptor enacts GO:0035020 regulation of Rac protein signal transduction.\n\nCellular placement is consistent with soluble assembly and cytoskeletal engagement. The absence of transmembrane features and the adaptor nature of BTB–Kelch proteins support a soluble cytoplasmic pool, aligning with GO:0005829 cytosol. During cytokinesis, Kelch adaptors often concentrate at the intercellular bridge; this explains enrichment at GO:0030496 midbody. The BTB–CUL3 interface situates the protein within GO:0031463 Cul3-RING ubiquitin ligase complex, which operates predominantly in the cytosol and at cytoskeletal hubs.\n\nMechanistically, the BTB domain recruits CUL3 and positions the RING E3 core; the BTB/Kelch-associated linker stabilizes this assembly; and the Kelch β-propeller selects substrates such as cytoskeletal regulators and Rac-pathway components. This causes K48-linked polyubiquitination and proteasomal clearance, thereby shaping cytoskeletal dynamics and signaling during processes like cytokinesis. I hypothesize that the adaptor transiently engages CUL3 and RBX1 to form the active ligase, captures substrates via the Kelch repeats, and cooperates with proteasome receptors to deliver ubiquitinated cargo. Likely partners include CUL3 and RBX1 as core ligase components; actin- and membrane-associated substrates; and Rac-pathway modulators that localize the complex to cytosolic and midbody compartments.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q8N4N3.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q8N4N3"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q8N4N3/entry","atlas":"/p/Q8N4N3"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}