{"uniprot":"Q9H7Z3","gene":"NRDE2","name":"Protein NRDE2 homolog","organism":"Homo sapiens (Human)","status":"dark","length":1164,"sequence":"MALFPAFAGLSEAPDGGSSRKELDWLSNPSFCVGSITSLSQQTEAAPAHVSEGLPLTRSHLKSESSDESDTNKKLKQTSRKKKKEKKKKRKHQHHKKTKRKHGPSSSSRSETDTDSEKDKPSRGVGGSKKESEEPNQGNNAAADTGHRFVWLEDIQAVTGETFRTDKKPDPANWEYKSLYRGDIARYKRKGDSCLGINPKKQCISWEGTSTEKKHSRKQVERYFTKKSVGLMNIDGVAISSKTEPPSSEPISFIPVKDLEDAAPVTTWLNPLGIYDQSTTHWLQGQGPPEQESKQPDAQPDSESAALKAKVEEFNRRVRENPRDTQLWMAFVAFQDEVMKSPGLYAIEEGEQEKRKRSLKLILEKKLAILERAIESNQSSVDLKLAKLKLCTEFWEPSTLVKEWQKLIFLHPNNTALWQKYLLFCQSQFSTFSISKIHSLYGKCLSTLSAVKDGSILSHPALPGTEEAMFALFLQQCHFLRQAGHSEKAISLFQAMVDFTFFKPDSVKDLPTKGQVEFFEPFWDSGEPRAGEKGARGWKAWMHQQERGGWVVINPDEDDDEPEEDDQEIKDKTLPRWQIWLAAERSRDQRHWRPWRPDKTKKQTEEDCEDPERQVLFDDIGQSLIRLSSHDLQFQLVEAFLQFLGVPSGFTPPASCLYLAMDENSIFDNGLYDEKPLTFFNPLFSGASCVGRMDRLGYPRWTRGQNREGEEFIRNVFHLVMPLFSGKEKSQLCFSWLQYEIAKVIWCLHTKNKKRLKSQGKNCKKLAKNLLKEPENCNNFCLWKQYAHLEWLLGNTEDARKVFDTALGMAGSRELKDSDLCELSLLYAELEVELSPEVRRAATARAVHILTKLTESSPYGPYTGQVLAVHILKARKAYEHALQDCLGDSCVSNPAPTDSCSRLISLAKCFMLFQYLTIGIDAAVQIYEQVFAKLNSSVFPEGSGEGDSASSQSWTSVLEAITLMHTSLLRFHMKVSVYPLAPLREALSQALKLYPGNQVLWRSYVQIQNKSHSASKTRRFFDTITRSAKPLEPWLFAIEAEKLRKRLVETVQRLDGREIHATIPETGLMHRIQALFENAMRSDSGSQCPLLWRMYLNFLVSLGNKERSKGVFYKALQNCPWAKVLYLDAVEYFPDEMQEILDLMTEKELRVRLPLEELELLLED","function_summary":"A nuclear scaffold that organizes RNA processing and export pathways. It concentrates in nuclear speckles and transiently in the nucleolus, where it assembles spliceosomal and RNA-surveillance machinery. By recruiting an MTR4-dependent axis and presenting a large helical-repeat surface, it coordinates pre-mRNA splicing with nuclear RNA export and restrains excessive RNA decay. This coupling of RNA maturation to surveillance and transport supports orderly progression through mitosis and contributes to cellular responses to DNA damage.","plain_language":"NRDE2 has barely been studied. The model's best guess: A nuclear scaffold that organizes RNA processing and export pathways. It concentrates in nuclear speckles and transiently in the nucleolus, where it assembles spliceosomal and RNA-surveillance machinery.","uniprot_summary":"May be involved in pre-mRNA splicing.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0000278","label":"mitotic cell cycle"},{"id":"GO:0006974","label":"cellular response to DNA damage stimulus"},{"id":"GO:0046824","label":"positive regulation of nucleocytoplasmic transport"},{"id":"GO:0046831","label":"regulation of RNA export from nucleus"},{"id":"GO:1902369","label":"negative regulation of RNA catabolic process"},{"id":"GO:0008380","label":"RNA splicing"}],"cellular_component":[{"id":"GO:0016607","label":"nuclear speck"},{"id":"GO:0005730","label":"nucleolus"}]},"interpro":[{"id":"IPR011990","name":"Tetratricopeptide-like helical domain superfamily","type":"homologous_superfamily","start":290,"end":1152},{"id":"IPR064703","name":"MTR4-interacting domain, NRDE-2, chordata","type":"domain","start":162,"end":258},{"id":"IPR013633","name":"siRNA-mediated silencing protein NRDE-2","type":"family","start":1,"end":1163}],"reasoning":"I begin with the InterPro architecture. The sequence is globally classified as IPR013633 (siRNA-mediated silencing protein NRDE-2 family) spanning residues 1–1163, establishing the overall identity and function class. Near the N-terminus lies IPR064703 (MTR4-interacting domain, NRDE-2, chordata) from residues 162–258; this discrete module dictates a high-affinity interface with the nuclear exosome cofactor MTR4, a hallmark of nuclear RNA surveillance and export pathways. The C-terminal two-thirds is dominated by IPR011990 (Tetratricopeptide-like helical domain superfamily) from residues 290–1152, a solenoidal array of helical repeats that creates an extended scaffold for multivalent macromolecular assembly. The ordered layout—an N-terminal MTR4-binding module feeding into a large TPR-like scaffold—causes avid, multivalent protein association rather than catalysis, directly supporting GO:0005515 protein binding as the molecular function.\n\nThis architecture dictates a nuclear RNA-processing hub. The MTR4-interacting domain recruits the MTR4/exosome axis, while the TPR-like scaffold nucleates assemblies with spliceosomal and RNA-handling factors. Such assemblies naturally couple pre-mRNA maturation and surveillance, explaining participation in GO:0008380 RNA splicing. By stabilizing and organizing RNA-processing complexes, the scaffold modulates the fate of nascent transcripts—promoting maturation, routing defective RNAs to decay, and coordinating handoff to export receptors. This coordination provides a mechanistic basis for GO:0046831 regulation of RNA export from nucleus and GO:1902369 negative regulation of RNA catabolic process, as the scaffold both restrains excessive decay and channels properly processed RNAs toward export.\n\nThe same assembly logic extends to cell-cycle and genome surveillance pathways. Nuclear RNA processing and exosome coupling feed into checkpoint pathways that sense transcriptional and DNA damage states. By stabilizing RNA–chromatin interfaces and tuning RNA maturation, the complex influences mitotic entry and fidelity checkpoints, aligning with GO:0000278 mitotic cell cycle and GO:0006974 cellular response to DNA damage stimulus.\n\nCellular localization follows from function and binding geography. The TPR-like scaffold and MTR4 interface drive accumulation in nuclear speckles—sites enriched for splicing and RNA export factors—matching GO:0016607 nuclear speck. Transient residence in the nucleolus is expected for RNA surveillance and ribonucleoprotein assembly, consistent with GO:0005730 nucleolus. Together, these nuclear territories define a soluble nuclear scaffold that concentrates in speckles and traffics through nucleolar subdomains.\n\nMechanistically, I hypothesize that the protein forms a nucleated platform that bridges MTR4/exosome modules with spliceosomal assemblies in speckles. By docking MTR4 via the NRDE-2 domain and presenting an extended TPR-like surface, it recruits and stabilizes RNA-binding and remodeling factors, thereby coordinating splicing completion with RNA export licensing and safeguarding transcriptomes during cell-cycle transitions and DNA damage responses. Likely partners include MTR4 itself and exosome subunits, core snRNP components, and speckle-resident splicing regulators, which together choreograph RNA maturation and nuclear export.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q9H7Z3.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q9H7Z3"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q9H7Z3/entry","atlas":"/p/Q9H7Z3"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}