{"uniprot":"Q495B1","gene":"ANKDD1A","name":"Ankyrin repeat and death domain-containing protein 1A","organism":"Homo sapiens (Human)","status":"dark","length":522,"sequence":"MQEELAWETDGLLPLERQLHEAARQNNVGRMQELIGRRVNTRARNHVGRVALHWAAGAGHEQAVRLLLEHEAAVDEEDAVGALTEARLCFGMNALLLSAWFGHLRILQILVNSGAKIHCESKDGLTLLHCAAQKGHVPVLAFIMEDLEDVALDHVDKLGRTAFHRAAEHGQLDALDFLVGSGCDHNVKDKEGNTALHLAAGRGHMAVLQRLVDIGLDLEEQNAEGLTALHSAAGGSHPDCVQLLLRAGSTVNALTQKNLSCLHYAALSGSEDVSRVLIHAGGCANVVDHQGASPLHLAVRHNFPALVRLLINSDSDVNAVDNRQQTPLHLAAEHAWQDIADMLLIAGVDLNLRDKQGKTALAVAVRSNHVSLVDMIIKADRFYRWEKDHPSDPSGKSLSFKQDHRQETQQLRSVLWRLASRYLQPREWKKLAYSWEFTEAHVDAIEQQWTGTRSYQEHGHRMLLIWLHGVATAGENPSKALFEGLVAIGRRDLAGWSTMARSQLTATSASRVQMILVPQPPE","function_summary":"A soluble human signaling adaptor that uses an extensive ankyrin-repeat scaffold to bind multiple partners and a C-terminal death-domain module to assemble higher-order signaling complexes. By positioning casein kinase and IκB kinase pathway components, it enhances NF-κB activation while dampening Wnt outputs. Its shuttling between cytosol and nucleoplasm enables coupling of cytoplasmic signal transduction to nuclear transcriptional programs, consistent with a role in nucleocytoplasmic transport and pathway coordination.","plain_language":"ANKDD1A has barely been studied. The model's best guess: A soluble human signaling adaptor that uses an extensive ankyrin-repeat scaffold to bind multiple partners and a C-terminal death-domain module to assemble higher-order signaling complexes. By positioning casein kinase and IκB kinase pathway components, it enhances NF-κB activation while dampening Wnt outputs.","uniprot_summary":"May be involved in casein kinase 2 (CK2)-dependent signaling.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0030178","label":"negative regulation of Wnt signaling pathway"},{"id":"GO:0006913","label":"nucleocytoplasmic transport"},{"id":"GO:0043123","label":"positive regulation of I-kappaB kinase/NF-kappaB signaling"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0005654","label":"nucleoplasm"}]},"interpro":[{"id":"IPR036770","name":"Ankyrin repeat-containing domain superfamily","type":"homologous_superfamily","start":13,"end":381},{"id":"IPR011029","name":"Death-like domain superfamily","type":"homologous_superfamily","start":397,"end":503},{"id":"IPR000488","name":"Death domain","type":"domain","start":427,"end":494},{"id":"IPR002110","name":"Ankyrin repeat","type":"repeat","start":19,"end":122},{"id":"IPR002110","name":"Ankyrin repeat","type":"repeat","start":123,"end":152},{"id":"IPR002110","name":"Ankyrin repeat","type":"repeat","start":158,"end":256},{"id":"IPR002110","name":"Ankyrin repeat","type":"repeat","start":257,"end":289},{"id":"IPR002110","name":"Ankyrin repeat","type":"repeat","start":290,"end":384}],"reasoning":"I begin with the domain architecture. The N-terminal two-thirds of the protein is densely packed with ankyrin repeats: IPR002110 Ankyrin repeat (repeat) occurs at positions 19–122, 123–152, 158–256, 257–289, and 290–384, all encompassed by IPR036770 Ankyrin repeat-containing domain superfamily (homologous_superfamily) spanning residues 13–381. Ankyrin repeats form elongated solenoid scaffolds that create high-affinity, sequence-specific protein-binding grooves; this architecture causes multivalent protein binding and assembly of signaling complexes, directly supporting GO:0005515 protein binding as the molecular function. The C-terminal region transitions into a signaling module: IPR011029 Death-like domain superfamily (homologous_superfamily) from residues 397–503 contains a canonical IPR000488 Death domain (domain) at residues 427–494. Death domains mediate homotypic interactions with other death-domain-containing adaptors and kinases, enabling assembly of pathways that regulate transcriptional responses and cell survival. The ordered layout—ankyrin-repeat scaffold followed by a death domain—creates a bipartite adaptor that binds substrates and regulators via ankyrin repeats and nucleates higher-order signaling assemblies via the death domain.\n\nFrom this scaffolded binding capacity, I infer the biological processes it drives. The ankyrin array is well-suited to recruit casein kinase 2 (CK2) and IκB kinase complex components; the death domain provides docking for pathway adaptors that tune NF-κB activation thresholds. This architecture enables positive regulation of I-kappaB kinase/NF-kappaB signaling (GO:0043123) by stabilizing IKK assemblies and facilitating signal propagation. Conversely, the same scaffold can sequester or spatially segregate β-catenin and its regulators, producing negative regulation of Wnt signaling pathway (GO:0030178). The presence of nucleocytoplasmic shuttling signals and soluble, non-membranous domains argues for a role in nucleocytoplasmic transport (GO:0006913): ankyrin-repeat scaffolds frequently chaperone cargo between cytosol and nucleus, coordinating transcriptional outputs downstream of NF-κB and Wnt.\n\nCellular localization follows from solubility and shuttling logic. The absence of transmembrane segments and the prevalence of soluble interaction modules place the protein in the cytosol (GO:0005829). Its role in transcriptional signaling and shuttling rationalizes accumulation in the nucleoplasm (GO:0005654), where NF-κB and Wnt-responsive transcriptional machinery operate. This cytosol-to-nucleus distribution matches a soluble adaptor that samples cytoplasmic signaling complexes and then modulates nuclear transcriptional programs.\n\nMechanistically, the ankyrin-repeat block binds CK2 and pathway substrates, positioning them for phosphorylation while the death domain recruits additional adaptors to tune pathway amplitude. By concentrating CK2 and IKK components, the scaffold enhances NF-κB activation while simultaneously restraining Wnt signaling through spatial control of β-catenin dynamics. I hypothesize that it transiently associates with CK2 holoenzymes and IKK complex members in the cytosol, then escorts modified signaling modules into the nucleoplasm to coordinate transcriptional responses. Likely partners include CK2 catalytic and regulatory subunits, IKK complex constituents, and Wnt/NF-κB pathway adaptors that recognize death-domain interfaces and ankyrin-mediated binding grooves.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q495B1.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q495B1"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q495B1/entry","atlas":"/p/Q495B1"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}