Dvir\GJ15622 (UniProt B4MAQ2) encodes the Drosophila virilis Exportin-5, a 1238-residue karyopherin-beta nuclear transport receptor. It is the one-to-one D. virilis ortholog of D. melanogaster Ranbp21 (Exp5), with which it shares the EXPORTIN-5 subfamily of the EXPORTIN 1/5 family and about 86% sequence identity along its whole length. The protein is a HEAT/ARM-repeat alpha-solenoid with an N-terminal importin-beta (IBN_N) Ran-binding region, an Xpo1-like region and a C-terminal Exportin-5 domain. Exportin-5 proteins bind their cargo together with RanGTP in the nucleus, carry it through the nuclear pore and release it in the cytoplasm when Ran hydrolyses GTP. Their cargoes are short structured RNAs, chiefly pre-miRNA hairpins and other minihelix-containing RNAs. Drosophila lacks an Exportin-t gene, so in D. melanogaster Exp5 binds tRNAs and pre-tRNAs as well as miRNA precursors, and it is required to maintain normal tRNA levels. No experiments have been done on the D. virilis protein itself; its function is inferred from its subfamily placement and from work on the D. melanogaster and human orthologs.
Summary: TreeGrafter transfer from PANTHER node PTN000131780, within the EXPORTIN-5 subfamily (PTHR11223:SF3). PAINT curators placed RNA binding on the exportin-5 clade node PTN000131750 (seeds: human XPO5 and mouse Xpo5). In D. melanogaster Exp5 (Ranbp21, same subfamily, 86% identity), PAR-CLIP directly captures tRNAs, pre-tRNAs, miRNA precursors and some mRNAs and lncRNAs.
Reason: Direct RNA binding is how Exportin-5 recognises its cargo, and the phylogenetic placement supports transferring it from the exportin-5 clade. More specific RNA-binding terms (tRNA binding, pre-miRNA binding) have experimental support in the orthologs, but PAINT propagated only the general term. The general term is kept here and the narrower ones are raised as a question.
Consistent with the idea that Exp5 is a major tRNA export receptor, we detected 343 PAR-CLIP clusters identified by Paralyzer at 295 tRNA loci
file:DROVI/B4MAQ2/B4MAQ2-uniprot.txt
PANTHER; PTHR11223:SF3; EXPORTIN-5; 1
file:DROVI/B4MAQ2/B4MAQ2-deep-research-falcon.md
Exportin-5 specializes as a RanGTP-dependent nuclear export receptor for double-stranded, minihelix RNA structures
GO:0005049 nuclear export signal receptor activity
IEA GO_REF:0000120
ACCEPT
Summary: An earlier version of this review removed this term as a CRM1-only function. That was a mistake. GO defines GO:0005049 as binding a nuclear export signal on a cargo to carry it through the nuclear pore, and says "The cargo can be either a RNA or a protein". In other words, it is the general molecular function of an exportin. PAINT placed this term at the family root node PTN000131749, with seeds from both subfamilies: XPO1 orthologs and the exportin-5 orthologs human XPO5 (Q9HAV4), mouse Xpo5 (MGI:1913789) and yeast MSN5 (SGD:S000002743). B4MAQ2 descends from that node. Human XPO5 has direct evidence for this activity: it binds cargo RanGTP-dependently and exports cargo in permeabilised cells.
Reason: This is the transport-receptor activity of an exportin, and the GO definition explicitly covers RNA cargo. The family-root PAINT node includes exportin-5 members, and B4MAQ2 is a full-length member of the EXPORTIN-5 subfamily. The earlier REMOVE misread the term as specific to protein NES recognition by CRM1, so it is reversed here.
Summary: PAINT placed nucleus at the family root node PTN000131749 (seeds include XPO5 and MSN5). Exportin-5 loads its cargo with RanGTP in the nucleus, and fly Exp5 binds nuclear tRNA precursors before their ends are processed.
Reason: An exportin has to be in the nucleus to load its cargo. This location follows from family-root PAINT placement and from the fly ortholog's binding of nuclear pre-tRNAs.
Summary: PAINT placed cytoplasm at the family root node PTN000131749 (seeds include human XPO5 and MSN5). Exportin-5 releases its cargo in the cytoplasm and shuttles between the two compartments.
Reason: Being in the cytoplasm is part of the shuttling transport cycle, and the term is supported by PAINT and by direct localisation of the human ortholog.
Summary: PAINT placed RNA export from nucleus on the exportin-5 clade node PTN000131750 (seeds: human XPO5, Arabidopsis HASTY, yeast MSN5). D. melanogaster Exp5 binds tRNAs and miRNA precursors in vivo, and knocking it down lowers tRNA abundance, which points to a role in tRNA export in a genus that has no Exportin-t.
Reason: Exporting structured RNA is the core process for Exportin-5. PAINT placement supports it, and so does the experimental work on the Drosophila ortholog. PAINT did not propagate the narrower terms pre-miRNA export or tRNA export, so this review stays at the PAINT-supported level.
Summary: This row comes from ARBA:ARBA00028564 together with the combined XPO1/5 InterPro entry IPR045065, not from PAINT. Human XPO5 can export dsRBD-containing proteins such as ILF3. However, PAINT curators did not place protein export from nucleus on the family root node or on the exportin-5 node (PTN000131749/PTN000131750); they placed protein-export biology only on the exportin-1 branch (ribosomal subunit export, PTN000131787). There is no evidence that Drosophila Exp5 exports protein cargo.
Reason: Protein export is a peripheral, mostly RNA-coupled activity of vertebrate XPO5. PAINT curators chose not to propagate it to the exportin-5 clade, and that omission is treated here as deliberate. The claim for the D. virilis protein rests on a family-level association rule rather than on phylogenetic transfer. The earlier REMOVE is softened because the claim is not contradicted for the subfamily.
Summary: This is an InterPro2GO mapping from the importin-beta N-terminal domain (IPR001494). That domain is shared by every karyopherin-beta, including importins whose cargo is protein. For an Exportin-5 receptor the documented cargo is mainly structured RNA. The protein moves between compartments itself, but the term describes moving protein cargo.
Reason: The domain-level mapping over-generalises from protein-cargo karyopherins. Protein transport is not the established function of the EXPORTIN-5 subfamily in Drosophila. The earlier MODIFY to RNA export from nucleus is replaced, because that term is already annotated and accepted directly.
Supporting Evidence:
file:DROVI/B4MAQ2/B4MAQ2-deep-research-falcon.md
most evidence-based prediction is transporter function for structured RNAs, not small molecules
Summary: This is an InterPro2GO mapping from the importin-beta N-terminal (Ran-binding) domain, which UniProt annotates at residues 34-100 of B4MAQ2. Every karyopherin-beta receptor binds RanGTP, and human XPO5 binds RanGTP directly.
Reason: Binding RanGTP is essential to the export cycle. A separate Ran-specific GTPase-binding term is not available in current GO (a search for "Ran GTPase binding" returns GO:0031267), so this term is already as specific as GO allows.
Summary: TreeGrafter transfer within the EXPORTIN-5 subfamily. Exportin-5, RanGTP and RNA cargo form a ternary export complex. Human XPO5 is annotated to this complex by IDA with pre-miRNA cargo.
Reason: The ternary exportin-RanGTP-RNA complex is how Exportin-5 carries out its transport function, and the transfer stays within the subfamily.
Supporting Evidence:
file:DROVI/B4MAQ2/B4MAQ2-deep-research-falcon.md
Exportin-5 binds cargo in cooperation with RanGTP, forming a trimeric export complex
Core Functions
RanGTP-dependent nuclear export receptor for structured RNAs. Exportin-5 binds minihelix-containing RNAs (in Drosophila, tRNAs, pre-tRNAs and pre-miRNAs) together with RanGTP in the nucleus, carries them through the nuclear pore complex, and releases them in the cytoplasm when Ran hydrolyses GTP.
Consistent with the idea that Exp5 is a major tRNA export receptor, we detected 343 PAR-CLIP clusters identified by Paralyzer at 295 tRNA loci
Binds the small GTPase Ran in its GTP-bound form through the N-terminal importin-beta region. RanGTP binding drives cargo loading in the nucleus and sets the direction of export.
Q: Should the Drosophila Exportin-5 clade carry tRNA export from nucleus (GO:0006409) and tRNA binding (GO:0000049) by phylogenetic transfer? Drosophila lacks Exportin-t, and fly Exp5 binds tRNAs in vivo. PAINT currently propagates only the general terms RNA binding and RNA export from nucleus.
Q: Is Dvir\GJ15622 the only Exportin-5 in D. virilis, and does it fully replace Exportin-t for tRNA export, as has been proposed for D. melanogaster Exp5?
Q: Does Drosophila Exp5 export any protein cargo independently of RNA, as vertebrate XPO5 does for dsRBD proteins? Or is the protein export described for XPO5 always coupled to RNA?
Suggested Experiments
Experiment: Perform PAR-CLIP or eCLIP in D. virilis cells to identify the RNA substrates bound by B4MAQ2 in vivo, followed by subcellular fractionation to confirm nucleocytoplasmic shuttling. Compare the RNA cargo profile to that reported for D. melanogaster Exportin-5.
Hypothesis: B4MAQ2 functions as a nuclear export receptor for pre-miRNAs and pre-tRNAs in D. virilis cells.
Type: PAR-CLIP/eCLIP with subcellular fractionation
Experiment: Express and purify recombinant B4MAQ2 and test RanGTP-dependent binding to pre-miRNA and tRNA substrates in vitro using electrophoretic mobility shift assays or fluorescence anisotropy.
Hypothesis: B4MAQ2 binds RanGTP and forms a trimeric export complex with structured RNA cargo.
Type: In vitro binding assay (EMSA/fluorescence anisotropy)
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.
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: The target contains Exportin-5-specific domain and subfamily assignments across a full-length transport-receptor architecture. Experiments in Drosophila establish Exportin-5-dependent export of nuclear pre-tRNAs to the cytoplasm (PMID:39098529), and heterokaryon assays show that human Exportin-5 shuttles between nucleus and cytoplasm (PMID:11777942), supporting cytoplasmic residence during the conserved transport cycle. This is a family-based localization inference and does not imply exclusive cytoplasmic localization. Cytoplasm is already present in cached GOA and UniProt.
Supporting Evidence:
file:DROVI/B4MAQ2/B4MAQ2-uniprot.txt: "ID B4MAQ2_DROVI Unreviewed; 1238 AA. ... DR InterPro; IPR045478; Exportin-5_C. ... DR PANTHER; PTHR11223:SF3; EXPORTIN-5; 1. ... FT DOMAIN 34..100 ... FT /note="Importin N-terminal" ... FT DOMAIN 114..274 ... FT /note="Exportin-1/Importin-beta-like" ... FT DOMAIN 319..1193 ... FT /note="Exportin-5 C-terminal""
PMID:39098529: "pre-tRNAs before end-processing were present in the cytoplasm"
PMID:11777942: "interacts with nucleoporins, and shuttles between the nuclear and cytoplasmic"