{"uniprot":"Q8N7U6","gene":"EFHB","name":"EF-hand domain-containing family member B","organism":"Homo sapiens (Human)","status":"dark","length":833,"sequence":"MNMEIGHPHEGKDDLGDKRVIMGTKFPMELGIRVGLGKEDSRCGESPVVSNKCEGRMAPPETKFPLSKGLEMGLERQNISRTVMQRGSLGVDSVSASQGTKPSLLPGRMGLENESLLAGYTHERIIQPPLGRVCGSSQAAGSRRAPLASGPEGVEELVGKPAFVMEPRQEMEKESTCVLMKPNTEIKLPVEVDIGLTQAEGPDETKNTEPQMGLVIEPPQCQFAQQHEQRKEAGNIESGVEPPDRIRPIYSGKFFDRTPCWPSAGKVIPVGYRVATCLTEKLPRLITPPEAKKYFNFRYPPAGVERVFYGRANDPQIAPYLTHGIRSKISVLANTLINPQPITTFQQKIKDKKESIYLSNRRAPLGKSHDQAPGLPKGMDTTNTTFGTAVIKEYSAKDVVNPPKSYEEVFKEGNEGHDLYVVSHNDYYAGEAKNRKYNPSSFHRCSVYGVPTPHFNDGRAMAKSLYWLHELQMKRGAKFVSKRADDFKEKFQHKLGRVLDPIAETMNVPPDCTFGACLRPEEYGVGDLIHNRLPDEYLRGKDRQRALIAAVRHHLKKVNYQKFDTLLAAFRHYDKKGDGMIDKDELQEACDQANLSLDDKLLDQLFDYCDVDNDGFINYLEFANFLNWKDKMLLKEYEERVIIKGRKPDCVNPTEANVEEPEQTLLIKPEDIVLKEAGSTEKTLRTLLRPSDKVSNYYKTTSSEINAIVGAIPSTCYPICGVPTIRSDIPAPRIRRISDRTNYGEEGSAYSLLYPTIFARKGVFERDFFKTRSKEEIAEILCNIGVKLSDEEFENVWNLASKKHHRGEVCVENIRNVLDELRHADRIKCKTLM","function_summary":"A calcium-sensing scaffold that uses multiple EF-hand modules to switch between conformations and regulate partner assembly at the foundation of the cilium. By coupling calcium binding to changes in affinity for cytoskeletal and membrane-associated complexes, it modulates calcium flux near the basal body and tunes endocytic and exocytic pathways. This Ca2+-responsive control likely dampens specific protein–protein interactions and tempers downstream calcineurin–NFAT signaling, thereby coordinating cilium-associated calcium handling and transport.","plain_language":"EFHB has barely been studied. The model's best guess: A calcium-sensing scaffold that uses multiple EF-hand modules to switch between conformations and regulate partner assembly at the foundation of the cilium. By coupling calcium binding to changes in affinity for cytoskeletal and membrane-associated complexes, it modulates calcium flux near the basal body and tunes endocytic and exocytic pathways.","uniprot_summary":"May be involved in endocytosis and/or exocytosis.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"},{"id":"GO:0005509","label":"calcium ion binding"}],"biological_process":[{"id":"GO:0032091","label":"negative regulation of protein binding"},{"id":"GO:0051924","label":"regulation of calcium ion transport"},{"id":"GO:0070884","label":"regulation of calcineurin-NFAT signaling cascade"}],"cellular_component":[{"id":"GO:0036064","label":"ciliary basal body"}]},"interpro":[{"id":"IPR011992","name":"EF-hand domain pair","type":"homologous_superfamily","start":483,"end":817},{"id":"IPR002048","name":"EF-hand domain","type":"domain","start":561,"end":632},{"id":"IPR057428","name":"EFHB, C-terminal EF-hand domain","type":"domain","start":750,"end":823},{"id":"IPR040193","name":"EF-hand domain-containing protein EFHC1/EFHC2/EFHB","type":"family","start":247,"end":831},{"id":"IPR018247","name":"EF-Hand 1, calcium-binding site","type":"binding_site","start":610,"end":622}],"reasoning":"I begin with the InterPro architecture. A broad family signature, IPR040193 (EF-hand domain-containing protein EFHC1/EFHC2/EFHB family, residues 247–831), frames the core of the polypeptide and points to a calcium-responsive scaffold class. Within this scaffold, IPR011992 (EF-hand domain pair homologous superfamily, residues 483–817) indicates a tandem EF-hand arrangement that typically mediates Ca2+-dependent conformational switching. The central module IPR002048 (EF-hand domain, residues 561–632) is reinforced by a defined Ca2+-coordinating loop, IPR018247 (EF-Hand 1, calcium-binding site, residues 610–622), which establishes a bona fide Ca2+-binding pocket. At the C-terminus, IPR057428 (EFHB, C-terminal EF-hand domain, residues 750–823) adds a second Ca2+-sensing unit that often tunes oligomerization and membrane-proximal interactions. The ordered layout—an extended EFHC-family scaffold carrying a central EF-hand pair and a specialized C-terminal EF-hand—creates a Ca2+-switchable platform that changes affinity for partner proteins.\n\nThis EF-hand architecture causes two primary molecular functions. First, the presence of multiple EF-hands with a validated Ca2+-binding loop supports GO:0005509 calcium ion binding. Second, EF-hand switches commonly regulate partner selection and assembly; thus the scaffold’s Ca2+-dependent surface remodeling supports GO:0005515 protein binding. Together, these features define a Ca2+-sensing adaptor that toggles between high- and low-affinity states for cytoskeletal and membrane-associated targets.\n\nFrom these molecular activities, the biological processes follow. A Ca2+-responsive adaptor at the centrosome and cilium can modulate ion handling by controlling the access of Ca2+ transport machinery to membranes and cytoskeletal anchors. This provides a mechanistic basis for GO:0051924 regulation of calcium ion transport. EF-hand–mediated conformational gating often reduces partner occupancy in certain states; such allosteric suppression is consistent with GO:0032091 negative regulation of protein binding. Because Ca2+ signaling cascades frequently route through calcineurin and NFAT, a Ca2+-sensing scaffold that sequesters or repositions partners can dampen this pathway, aligning with GO:0070884 regulation of calcineurin-NFAT signaling cascade.\n\nCellular placement is dictated by both the EFHC family’s known cytoskeletal association and the need to regulate Ca2+ flux near microtubule-organizing structures. The architecture and functional logic point to the cilium-organizing hub and its foundation, supporting localization to GO:0036064 ciliary basal body. Occupancy at the basal body positions the protein to influence intraflagellar transport initiation and membrane-proximal Ca2+ handling.\n\nMechanistically, I propose that Ca2+ binding at residues 610–622 and the C-terminal EF-hand (750–823) toggles the scaffold between compact and extended conformations that alternately mask or expose interaction grooves. In the basal body environment, this switch likely controls assembly of membrane–cytoskeleton junctions that gate Ca2+ entry and endocytic/exocytic flux. By transiently reducing partner affinity (negative regulation of protein binding), the adaptor can pause complex formation until local Ca2+ rises, thereby coordinating cilium-associated Ca2+ signaling and restraining calcineurin-NFAT throughput.\n\nLikely interaction partners follow from this model: basal body and centriolar satellite organizers (e.g., PCM1 and CEP proteins) that anchor the scaffold; membrane trafficking modules (RAB5 and RAB11 pathways) that tune endocytic routes; and Ca2+-handling assemblies (STIM1/ORAI1) that set local Ca2+ thresholds. These associations would collectively situate the EF-hand scaffold as a Ca2+-dependent organizer of ciliary basal body function and Ca2+ transport control.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q8N7U6.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q8N7U6"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q8N7U6/entry","atlas":"/p/Q8N7U6"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}