{"uniprot":"Q7Z6M1","gene":"RABEPK","name":"Rab9 effector protein with kelch motifs","organism":"Homo sapiens (Human)","status":"dark","length":372,"sequence":"MKQLPVLEPGDKPRKATWYTLTVPGDSPCARVGHSCSYLPPVGNAKRGKVFIVGGANPNRSFSDVHTMDLGKHQWDLDTCKGLLPRYEHASFIPSCTPDRIWVFGGANQSGNRNCLQVLNPETRTWTTPEVTSPPPSPRTFHTSSAAIGNQLYVFGGGERGAQPVQDTKLHVFDANTLTWSQPETLGNPPSPRHGHVMVAAGTKLFIHGGLAGDRFYDDLHCIDISDMKWQKLNPTGAAPAGCAAHSAVAMGKHVYIFGGMTPAGALDTMYQYHTEEQHWTLLKFDTLLPPGRLDHSMCIIPWPVTCASEKEDSNSLTLNHEAEKEDSADKVMSHSGDSHEESQTATLLCLVFGGMNTEGEIYDDCIVTVVD","function_summary":"A cytosolic kelch beta-propeller scaffold that functions as a Rab9-directed effector in human cells. It assembles multivalent protein complexes that regulate endosomal sorting and vesicle traffic, coupling receptor-mediated endocytosis with docking and handoff of cargo toward the trans-Golgi network. By cycling between the cytosol and endosomal/transport vesicle membranes, it stabilizes Rab9-dependent assemblies that coordinate vesicle tethering and maturation en route to the Golgi apparatus.","plain_language":"RABEPK has barely been studied. The model's best guess: A cytosolic kelch beta-propeller scaffold that functions as a Rab9-directed effector in human cells. It assembles multivalent protein complexes that regulate endosomal sorting and vesicle traffic, coupling receptor-mediated endocytosis with docking and handoff of cargo toward the trans-Golgi network.","uniprot_summary":"May be involved in several stages of intracellular trafficking.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0006904","label":"vesicle docking involved in exocytosis"},{"id":"GO:0006898","label":"receptor-mediated endocytosis"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0005768","label":"endosome"},{"id":"GO:0030133","label":"transport vesicle"},{"id":"GO:0032588","label":"trans-Golgi network membrane"}]},"interpro":[{"id":"IPR015915","name":"Kelch-type beta-propeller","type":"homologous_superfamily","start":12,"end":314},{"id":"IPR052124","name":"Rab9 effector with kelch motifs","type":"family","start":1,"end":372}],"reasoning":"I begin with the InterPro architecture. The N-terminal to central region (residues 12–314) forms IPR015915, a Kelch-type beta-propeller homologous superfamily. Kelch propellers create rigid, solvent-exposed blades that mediate high-specificity protein–protein interactions and often act as cytosolic scaffolds that dock onto membranes via small GTPases or acidic membrane patches. Encompassing essentially the full length of the polypeptide (residues 1–372), IPR052124 classifies the protein as a Rab9 effector with kelch motifs. This family assignment ties the propeller scaffold to a Rab9-centered trafficking axis. The ordered layout—an N-terminal kelch propeller embedded within a Rab9-effector framework—causes avid, multivalent protein binding rather than catalysis, supporting GO:0005515 protein binding as the molecular function.\n\nA kelch beta-propeller that operates as a Rab9 effector naturally organizes endosomal sorting and vesicle traffic. By binding Rab9-positive membranes and assembling accessory factors, the scaffold promotes cargo progression from early to late endosomes and onward to the trans-Golgi network. This assembly role directly supports vesicle tethering and docking steps that precede fusion, aligning with GO:0006904 vesicle docking involved in exocytosis. The same architecture also explains participation in GO:0006898 receptor-mediated endocytosis: Rab9-dependent pathways govern receptor cargo sorting and recycling. Thus, the kelch-propeller scaffold integrates endocytic uptake with downstream endosome-to-TGN transport.\n\nCellular localization follows from this trafficking logic. A soluble propeller scaffold without transmembrane segments resides in the cytosol (GO:0005829 cytosol) but is recruited to membranes through Rab9 and associated adaptors. Its operational stage is the endosome (GO:0005768 endosome) and transport vesicle (GO:0030133 transport vesicle), culminating at the trans-Golgi network membrane (GO:0032588 trans-Golgi network membrane). This cytosol-to-membrane cycle is dictated by the Rab9 effector identity and the kelch-mediated binding surfaces.\n\nMechanistically, the kelch propeller provides a multivalent platform that captures Rab9 and accessory complexes to choreograph vesicle docking and cargo sorting. I hypothesize that it binds Rab9A/B on endosomal membranes, recruits tethering/fusion modules, and transiently couples to TGN-directed transport vesicles. Likely partners include Rab9 itself and endosomal sorting assemblies; by stabilizing these interactions, the scaffold times vesicle tethering and receptor cargo handoff from endosomes to the TGN, thereby coupling endocytosis with exocytic routes.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q7Z6M1.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q7Z6M1"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q7Z6M1/entry","atlas":"/p/Q7Z6M1"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}