Affinage

IPO5

Importin-5 · UniProt O00410

Round 2 corrected
Length
1097 aa
Mass
123.6 kDa
Annotated
2026-04-28
57 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IPO5 (RanBP5) is an importin-β family nuclear transport receptor that mediates RanGTP-dependent import of diverse cargo proteins—including ribosomal proteins, the maternal factor PGC7/Stella, RNA-binding proteins CPEB3 and Musashi-1, RASAL2, and viral polymerase subunits—through the nuclear pore complex (PMID:9687515, PMID:17143267, PMID:22730302). Its HEAT-repeat architecture forms an extended NLS-binding surface, as revealed by crystal and cryo-EM structures, that recognizes basic NLS sequences in an unstructured, wrapped conformation (PMID:32222384, PMID:39536408). Upstream signaling modulates IPO5 activity: NMDAR-driven RanBP1 upregulation enhances CPEB3 nuclear import by reducing cytoplasmic RanGTP (PMID:22730302). Conditional knockout studies in mice establish that IPO5 is essential for early embryogenesis and male germline development, with its loss causing meiotic failure and germ-cell depletion (PMID:40652294).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1997 High

    Discovery of IPO5 as a RanGTP-binding, importin-β-related protein that associates with nuclear pores established a new non-classical nuclear import pathway.

    Evidence Overlay assays, yeast two-hybrid, GTPase assays, subcellular fractionation, and NPC binding assays in mammalian cells

    PMID:9271386

    Open questions at the time
    • No cargo identified at this stage
    • Mechanism of RanGTP-dependent cargo release unknown
    • In vivo function not assessed
  2. 1998 High

    Demonstration that IPO5 directly binds and imports ribosomal proteins via very basic NLS motifs revealed its first physiological cargoes and showed redundancy among multiple import receptors.

    Evidence Reconstituted in vitro nuclear import assays in digitonin-permeabilized cells with recombinant ribosomal proteins and multiple importins

    PMID:9687515

    Open questions at the time
    • Relative contribution of each importin in vivo unclear
    • No structural detail of NLS recognition
    • Non-ribosomal cargoes unknown
  3. 2006 High

    Identification of PGC7/Stella as an IPO5 cargo linked nuclear transport to epigenetic protection of maternal DNA methylation imprints, revealing a developmental role.

    Evidence Co-IP, yeast two-hybrid, mutant rescue, and in vivo nuclear localization assays in mouse embryos

    PMID:17143267

    Open questions at the time
    • NLS motif on PGC7 not precisely mapped
    • Whether IPO5 is the sole import receptor for PGC7 not resolved
    • In vivo IPO5 loss-of-function phenotype in embryos not tested
  4. 2012 High

    Elucidation of NMDAR-RanBP1-RanGTP axis controlling CPEB3 nuclear import via IPO5 established that signaling pathways dynamically regulate IPO5 cargo transport in neurons.

    Evidence Co-IP, GST pulldown, subcellular fractionation, NMDA stimulation, and RanBP1 overexpression in neuronal cells

    PMID:22730302

    Open questions at the time
    • Whether other neuronal cargoes are co-regulated not explored
    • Structural basis of RRM1-IPO5 interaction unknown
    • Physiological consequence in synaptic plasticity not directly tested
  5. 2015 Medium

    IPO5-mediated nuclear import of Musashi-1 to the XY chromatin domain in pachytene spermatocytes linked IPO5 to male germline posttranscriptional regulation.

    Evidence Co-IP, immunofluorescence, and transgenic MSI1 overexpression mouse model in testis

    PMID:25782991

    Open questions at the time
    • Single-lab study; independent confirmation needed
    • Whether IPO5 loss disrupts MSI1 localization not tested genetically
    • Specific NLS on MSI1 not mapped
  6. 2016 High

    Biochemical reconstitution and SAXS modeling of the influenza PA–PB1–IPO5 stoichiometric complex showed that viral polymerase exploits IPO5 for nuclear entry, and IPO5 binding competitively prevents vRNA association.

    Evidence Co-expression, affinity purification, SAXS, gel filtration, and RNA-binding assays with recombinant influenza polymerase subunits

    PMID:27095520

    Open questions at the time
    • Atomic-resolution structure of the ternary complex not available at this time
    • In vivo relevance for viral replication not directly tested
    • Whether host cell deploys this competition as an antiviral mechanism unknown
  7. 2020 High

    Crystal structures of ligand-free IPO5 isoforms revealed the HEAT-repeat architecture and NLS-binding surface; mutagenesis confirmed residues critical for influenza PB1 binding.

    Evidence X-ray crystallography, NLS docking, point mutagenesis, binary protein complementation assay

    PMID:32222384

    Open questions at the time
    • No cargo-bound structure at this time
    • NLS recognition mode for endogenous cargoes not structurally defined
    • Conformational changes upon cargo/RanGTP binding not captured
  8. 2022 High

    PCV2 capsid protein was shown to bind IPO5 via specific residues (Cap R24–IPO5 P709), revealing that IPO5 not only imports viral components but also shields them from proteasomal degradation.

    Evidence Co-IP/MS, GST pulldown, site-directed mutagenesis, proteasome inhibitor rescue, cycloheximide chase, viral replication assays

    PMID:36409110

    Open questions at the time
    • Non-canonical chaperone-like stabilization mechanism not structurally explained
    • Whether similar stabilization occurs for endogenous cargoes unknown
    • Generalizability to other viral capsid proteins untested
  9. 2024 High

    A 3.2 Å cryo-EM structure of the IPO5–PB1 NLS complex defined the molecular basis of NLS recognition, showing the NLS adopts an extended, non-secondary-structure conformation wrapped along the HEAT solenoid.

    Evidence Cryo-EM structure determination with mutagenesis of binding interface residues and biochemical validation

    PMID:39536408

    Open questions at the time
    • Structure of IPO5 in complex with endogenous (non-viral) NLS cargo not yet determined
    • RanGTP-induced cargo release mechanism not structurally captured
    • Whether all IPO5 cargoes use the same binding groove not known
  10. 2025 High

    Conditional knockout studies definitively established IPO5 as essential for embryogenesis and male meiosis; IP-MS in testes identified SFPQ and XPO2 as novel partners, suggesting cargo shuttling circuits involving IPO5.

    Evidence CMVCre, VasaCre, and Stra8Cre conditional knockouts in mice; IP-MS from fetal testes and spermatocytes; histology

    PMID:40652294

    Open questions at the time
    • Molecular cargoes responsible for the embryonic lethality not identified
    • Functional significance of IPO5–XPO2 interaction not mechanistically dissected
    • Whether female-specific cargoes exist but are dispensable remains unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IPO5 discriminates among its diverse cargoes and whether its non-canonical protein stabilization function extends beyond viral capsids to endogenous substrates remain open questions.
  • No systematic cargo selectivity model or comprehensive cargo inventory
  • Structural basis of RanGTP-induced cargo release not captured for IPO5
  • Chaperone-like stabilization activity not tested for endogenous cargoes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0038024 cargo receptor activity 5
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-9609507 Protein localization 6 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2
Partners
CPEB3MSI1PGC7RANBP1RASAL2SFPQXPO2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RanBP5 (IPO5) was identified as a novel 124-kDa importin-β-related protein that binds RanGTP and forms a trimeric RanBP1–Ran–RanBP5 complex. It localizes predominantly to the cytoplasm, can bind nuclear pore complexes, and was proposed to mediate a nucleocytoplasmic transport pathway distinct from the classical importin-α-dependent NLS pathway. Overlay assay with RanGTP, yeast two-hybrid with RanBP1 as bait, GTPase assays, subcellular fractionation, nuclear pore binding assays Molecular and cellular biology High 9271386
1998 RanBP5 (IPO5), together with importin-β, transportin, and RanBP7, directly binds and imports ribosomal proteins (rpL23a, rpS7, rpL5) into the nucleus in mammalian cells via a very basic domain on the ribosomal proteins that serves as an archetypal import signal. Each of the four receptors can alternatively import the same ribosomal protein. In vitro nuclear import assays in digitonin-permeabilized cells, direct binding assays (pulldown), recombinant protein reconstitution The EMBO journal High 9687515
2006 PGC7/Stella, a maternal factor essential for early embryogenesis, binds to RanBP5 (IPO5) and uses this interaction for nuclear localization. Nuclear entry of PGC7/Stella via RanBP5 is required for it to protect maternal genome DNA methylation imprints from demethylation after fertilization. Co-immunoprecipitation, yeast two-hybrid, mutant rescue experiments, in vivo nuclear localization studies Nature cell biology High 17143267
2012 IPO5 facilitates nuclear import of the RNA-binding protein CPEB3 by binding directly to CPEB3's RRM1 domain. NMDAR signaling increases RanBP1 expression and reduces cytoplasmic RanGTP levels, enhancing CPEB3–IPO5 interaction and thereby accelerating CPEB3 nuclear import to modulate Stat5b-dependent transcription in neurons. Co-immunoprecipitation, GST pulldown, subcellular fractionation, immunofluorescence, RanBP1 overexpression, NMDA stimulation assays Nucleic acids research High 22730302
2015 IPO5 physically interacts with the RNA-binding protein Musashi-1 (MSI1) and facilitates its nuclear translocation to the transcriptionally silenced XY chromatin domain in meiotic pachytene spermatocytes. This nuclear import event releases MSI1 from its RNA-binding targets and is important for posttranscriptional regulation during early spermatogenesis. Co-immunoprecipitation, transgenic Msi1 overexpression mouse model, immunofluorescence, expression studies in testis FASEB journal Medium 25782991
2016 The influenza A virus PA–PB1 heterodimer forms a stable, stoichiometric complex with host RanBP5 (IPO5), as demonstrated by SAXS modelling. This PA–PB1–RanBP5 complex loses the ability to bind 5'-vRNA, suggesting that RanBP5-mediated nuclear import of the viral polymerase submodule is regulated by competitive binding. Polyprotein co-expression strategy, affinity purification, SAXS, gel filtration, binding assays Scientific reports High 27095520
2019 IPO5 binds to the NLS sequence of RASAL2 and mediates its nuclear translocation in colorectal cancer cells. This transport activates RAS signaling and promotes colorectal cancer progression. IPO5 was identified as a cargo-binding partner of RASAL2 by mass spectrometry and confirmed by Co-IP. Mass spectrometry interactome screen, Co-IP, subcellular fractionation, immunofluorescence, in vivo xenograft, shRNA knockdown Journal of experimental & clinical cancer research Medium 31288861
2020 Crystal structures of two distinct ligand-free isoforms of human RanBP5 (IPO5) were determined, revealing the general HEAT-repeat architecture of the IMB3 karyopherin-β subfamily and highlighting structural differences from the yeast orthologue Kap121p. Point mutations in the NLS-binding surface suppress influenza PA–PB1 binding in a binary protein complementation assay. X-ray crystallography, NLS docking, point mutagenesis, binary protein complementation assay Journal of molecular biology High 32222384
2022 IPO5 promotes malignant progression of esophageal cancer by activating the RAS–ERK signaling pathway and inducing epithelial-mesenchymal transition (EMT). Knockdown of IPO5 arrested cells in G2/M phase, reduced tumor growth in vivo, and decreased downstream RAS pathway protein levels. Lentiviral shRNA knockdown, CCK-8 proliferation assay, Transwell invasion assay, flow cytometry, subcutaneous xenograft, Western blot for RAS–ERK pathway components and EMT markers Oxidative medicine and cellular longevity Medium 36120598
2022 The PCV2 capsid protein (Cap) binds directly to IPO5, with arginine-24 of Cap interacting with proline-709 of IPO5. IPO5 promotes nuclear import of incoming PCV2 virions and also prevents proteasomal degradation of newly synthesized Cap protein, thereby stabilizing it and supporting virus replication. Co-immunoprecipitation with mass spectrometry, GST pulldown, site-directed mutagenesis (R24 and P709), IPO5 knockdown with proteasome inhibitor rescue, cycloheximide chase assay, viral replication assays Journal of virology High 36409110
2024 Cryo-EM structure at 3.2 Å resolution of the RanBP5 (IPO5)–PB1 NLS domain complex revealed that the PB1 NLS does not adopt secondary structure and interacts with RanBP5 in a wrapped/extended conformation. Mutagenesis identified critical amino acid residues at the binding interface. Cryo-EM structure determination (3.2 Å), mutagenesis of binding interface residues, biochemical binding assays Biochemical and biophysical research communications High 39536408
2025 Global and conditional knockout of IPO5 in mice demonstrated it is essential for early embryogenesis (global CMVCre deletion produced no null embryos at E12.5) and specifically required for male germline development (VasaCre deletion caused adult testes to lack germ cells, while female fertility was unaffected). Stra8Cre-directed deletion caused meiotic failure. Novel IPO5 binding partners identified by immunoprecipitation/mass spectrometry include SFPQ in fetal testes and XPO2 (exportin 2) in spermatocytes and spermatids, implicating IPO5 in cargo shuttling including Stella and BMP-signaling SMADs 1/5/9. Conditional knockout mice (CMVCre, VasaCre, Stra8Cre), immunoprecipitation coupled with mass spectrometry, histology, spermatocyte isolation Biology of reproduction High 40652294

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2005 Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 996 15758953
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
1993 A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 708 8105392
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
1992 Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proceedings of the National Academy of Sciences of the United States of America 513 1631159
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2006 PGC7/Stella protects against DNA demethylation in early embryogenesis. Nature cell biology 433 17143267
2001 Karyopherins and nuclear import. Current opinion in structural biology 433 11751052
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
1998 Importin beta, transportin, RanBP5 and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells. The EMBO journal 430 9687515
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
1997 HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proceedings of the National Academy of Sciences of the United States of America 415 9275210
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2004 14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. The Biochemical journal 372 14744259
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2015 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. The EMBO journal 362 25796446
1998 Phosphorylation regulates association of the transcription factor Pho4 with its import receptor Pse1/Kap121. Genes & development 206 9732266
1997 Ran-binding protein 5 (RanBP5) is related to the nuclear transport factor importin-beta but interacts differently with RanBP1. Molecular and cellular biology 75 9271386
1999 Multidrug-resistant human and animal Salmonella typhimurium isolates in France belong predominantly to a DT104 clone with the chromosome- and integron-encoded beta-lactamase PSE-1. The Journal of infectious diseases 63 10191220
1990 The human U1 snRNA promoter correctly initiates transcription in vitro and is activated by PSE1. Genes & development 47 2125285
1991 Sequence of the PSE-1 beta-lactamase gene. Antimicrobial agents and chemotherapy 44 1804019
2012 NMDAR signaling facilitates the IPO5-mediated nuclear import of CPEB3. Nucleic acids research 42 22730302
2001 Pse1/Kap121-dependent nuclear localization of the major yeast multidrug resistance (MDR) transcription factor Pdr1. Molecular microbiology 41 11136452
2014 Molecular Screening of Keratoconus Susceptibility Sequence Variants in VSX1, TGFBI, DOCK9, STK24, and IPO5 Genes in Polish Patients and Novel TGFBI Variant Identification. Ophthalmic genetics 39 24940934
2019 IPO5 promotes the proliferation and tumourigenicity of colorectal cancer cells by mediating RASAL2 nuclear transportation. Journal of experimental & clinical cancer research : CR 36 31288861
2011 Simultaneous saccharification and fermentation of Kanlow switchgrass by thermotolerant Kluyveromyces marxianus IMB3: the effect of enzyme loading, temperature and higher solid loadings. Bioresource technology 36 21955879
1992 Screening and identification of a gene, PSE-1, that affects protein secretion in Saccharomyces cerevisiae. Journal of cell science 36 1522152
2015 RNA binding protein Musashi-1 directly targets Msi2 and Erh during early testis germ cell development and interacts with IPO5 upon translocation to the nucleus. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 25782991
2016 Structural characterization of recombinant IAV polymerase reveals a stable complex between viral PA-PB1 heterodimer and host RanBP5. Scientific reports 24 27095520
2016 The PSE1 gene modulates lead tolerance in Arabidopsis. Journal of experimental botany 24 27335453
2015 The ß-importin KAP8 (Pse1/Kap121) is required for nuclear import of the cellulase transcriptional regulator XYR1, asexual sporulation and stress resistance in Trichoderma reesei. Molecular microbiology 19 25626518
2022 IPO5 Mediates EMT and Promotes Esophageal Cancer Development through the RAS-ERK Pathway. Oxidative medicine and cellular longevity 18 36120598
2006 A combined effect of the KPNA3 and KPNB3 genes on susceptibility to schizophrenia. Neuroscience letters 12 16644122
2020 X-ray Structure of the Human Karyopherin RanBP5, an Essential Factor for Influenza Polymerase Nuclear Trafficking. Journal of molecular biology 9 32222384
2020 IPO5 promotes malignant progression of esophageal cancer through activating MMP7. European review for medical and pharmacological sciences 8 32373960
2019 Novel influenza inhibitors designed to target PB1 interactions with host importin RanBP5. Antiviral research 7 30742842
2002 Iminodiacetate and nitrilotriacetate degradation by Kluyveromyces marxianus IMB3. Biochemical and biophysical research communications 7 11785972
2022 Porcine Circovirus Type 2 Hijacks Host IPO5 to Sustain the Intracytoplasmic Stability of Its Capsid Protein. Journal of virology 6 36409110
2024 Structural insights into Influenza A virus RNA polymerase PB1 binding to nuclear import host factor RanBP5. Biochemical and biophysical research communications 2 39536408
2010 Genetic and functional study of the IPO5 gene in schizophrenia. Psychiatry research 2 20542336
1996 Short communication: Ethanol production from cellulose at 45°C using a batch-fed system containing alginate-immobilized Kluyveromyces marxianus IMB3. World journal of microbiology & biotechnology 2 24415101
2025 The nuclear transport factor IPO5 revealed as a critical mediator of male germline development†. Biology of reproduction 1 40652294