FTZ-F1 is an NR5A-family nuclear transcription factor that recognizes specific DNA elements and controls developmental gene expression in Drosophila. Alternative N-terminal isoforms share the DNA-binding and C-terminal regulatory domains. The beta developmental product represented by M9NFK2 provides temporal competence for ecdysone-responsive transcription during molting and metamorphosis and participates in feedback regulation of its expression. FTZ-F1 can activate transcription without an added small-molecule ligand; its regulatory domain binds the Ftz cofactor and has a dynamic pocket capable of phospholipid binding in vitro.
Summary: FTZ-F1 regulates RNA polymerase II transcription through sequence-specific DNA binding.
Reason: Purified FTZ-F1 binds regulatory DNA, and disruption of its recognition site reduces reporter expression in embryos (PMID:2113881). The exact 803-aa product is identical to reviewed P33244-2 and retains the common DNA-binding and cofactor-interaction domains. This biological evidence supports the activity independently of the ARBA source of this row.
Summary: The DNA interaction is sequence-specific binding to RNA polymerase II cis-regulatory elements.
Reason: True but uninformative. FTZ-F1 was purified by its binding to a recognition element in the upstream regulatory region of the RNA polymerase II-transcribed segmentation gene ftz, and mutation of that site reduced reporter expression (PMID:2113881). Mammalian NR5A proteins from the same PANTHER family likewise bind DNA as monomers and activate transcription (PMID:23340581). RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978, an is_a descendant of GO:0003677 and GO:0043565) is the precise supported term; it is also the term PAINT assigns at the NR5A node for the canonical FTZ-F1 entry. M9NFK2 retains the complete DNA-binding domain.
Summary: Nuclear-receptor family membership is established; ligand-regulated transcription is not established.
Reason: QuickGO defines GO:0004879 as DNA-binding transcription factor activity regulated by ligand binding. FTZ-F1 has well-supported transcriptional activity in the absence of added ligand, and its crystal structure contains an intramolecular helix in the canonical pocket (PMID:21775434). Solution NMR and lipid-binding experiments demonstrate a dynamic pocket and phospholipid binding (PMID:29547262), so an absolute inability to bind ligands would be incorrect. However, these findings do not demonstrate ligand-dependent transcriptional regulation. The experimentally established RNA polymerase II transcription factor activity is the appropriate supported assignment; family terminology alone does not meet the GO definition. Evolutionary grounding agrees. M9NFK2 sits in PANTHER subfamily PTHR24086:SF15 with canonical FTZ-F1, Bombyx FTZ-F1 and C. elegans nhr-25, whereas the lipid-regulated mammalian NR5A2/LRH-1 and steroidogenic NR5A1/SF-1 are in separate subfamilies (SF18, SF24), so their ligand-regulation properties are not transferred. The PAINT annotations of the canonical FTZ-F1 entry at the NR5A node include cis-regulatory DNA binding and regulation of RNA polymerase II transcription but not nuclear receptor activity, which is read here as a deliberate curatorial omission.
Reason: Immunolocalization places betaFTZ-F1 in nuclei before larval ecdysis and pupation (PMID:11060234), and chromosome staining identifies many bound loci (PMID:8096644). M9NFK2 matches P33244-2, whose isoform-specific sequence is assigned to the developmental isoform characterized by Lavorgna et al. These findings support nuclear localization of this product.
Summary: FTZ-F1 regulates transcription rather than catalyzing RNA synthesis.
Reason: Participation in transcription is broadly compatible with its role, but regulation of RNA polymerase II transcription expresses the established molecular contribution more precisely. FTZ-F1 DNA-site mutation reduces target reporter transcription (PMID:2113881).
The results suggest that FTZ-F1 is a transcriptional activator necessary for the proper expression of the ftz gene.
GO:0006355 regulation of DNA-templated transcription
IEA GO_REF:0000120
MODIFY
Summary: The transcriptional regulation concerns RNA polymerase II genes.
Reason: FTZ-F1 controls developmental protein-coding genes, including the ecdysone-response gene hierarchy. The RNA polymerase II-specific regulatory process is more informative than the parent transcription-regulation term (PMID:2113881; PMID:7954827).
We show that beta FTZ-F1 represses its own transcription and is repressed by ecdysone
GO:0006357 regulation of transcription by RNA polymerase II
IEA GO_REF:0000108
ACCEPT
Summary: FTZ-F1 controls expression of developmental target genes.
Reason: DNA-binding and reporter experiments establish direct transcriptional activation, while betaFTZ-F1 also participates in negative feedback on its own expression (PMID:2113881; PMID:7954827). The sign of regulation depends on target and developmental context; the general regulatory process is appropriate.
Summary: Zinc coordination supports the nuclear-receptor DNA-binding fold.
Reason: The exact sequence contains the C4 nuclear-receptor zinc-finger DNA-binding domain at residues 281–356, supported by PROSITE and InterPro feature assignments. Zinc coordination is a structural property of this domain, not the distinguishing physiological activity of FTZ-F1.
Summary: Beta FTZ-F1 participates in the intracellular ecdysone-response pathway.
Reason: The term describes a signaling pathway initiated by an intracellular ligand-receptor interaction; a participant need not itself bind the initiating hormone. BetaFTZ-F1 supplies competence for the ecdysone-induced transcriptional cascade and controls its stage-specific response (PMID:7954827). Its downstream role supports pathway participation without implying that FTZ-F1 is an ecdysone or thyroid-hormone binding receptor.
Summary: The relevant signal-transduction role is intracellular endocrine transcriptional signaling.
Reason: BetaFTZ-F1 confers competence for the ecdysone-triggered developmental transcriptional response (PMID:7954827). Intracellular receptor signaling pathway describes this role more precisely than unrestricted intracellular signal transduction. The support comes from the developmental experiments, not agreement with the ARBA assertion.
Summary: FTZ-F1 recognizes specific cis-regulatory DNA sequences of RNA polymerase II genes.
Reason: Correct but less specific than the evidence supports. Purification, DNA-binding-site mutagenesis, and reporter expression establish recognition of an FTZ-F1 element in the cis-regulatory region of the RNA polymerase II-transcribed ftz gene (PMID:2113881), so the is_a descendant GO:0000978 (also used in the MODIFY of the generic DNA binding row) is the precise term. The 803-aa product retains the same DNA-binding domain as the longer canonical product; the isoforms differ only upstream of that shared domain.
Q: Which physiological phospholipids, if any, regulate full-length betaFTZ-F1 transcriptional activity, rather than merely binding its isolated regulatory domain?
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
The ProtNLM2 API snapshot retrieved 2026-09-08 contains no GO-term predictions for M9NFK2. The gene review accepts DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981) and nucleus (GO:0005634) for this product, supported by primary FTZ-F1 DNA-binding/reporter experiments, betaFTZ-F1 nuclear localization and exact sequence identity to reviewed P33244-2. Both terms are already in GOA for M9NFK2, so their omission loses no novel information; had either been emitted it would score CNN. Nuclear-receptor family membership alone does not establish ligand-regulated transcription, and the gene review modifies nuclear receptor activity (GO:0004879) to GO:0000981 on that basis. The separate ProtNLM2 FUNCTION paragraph supports broad transcriptional regulation but carries a PLI judgment for high-affinity thyroid-hormone receptor specificity, which derives from a thyroid hormone receptor phmmer hit (Q91279) rather than the NR5A subfamily. This completed record assesses the absence of GO output; predictions is empty because no GO or EC prediction was emitted. The narrative judgments remain in the linked function review and are not scores assigned to the omission.