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IPO13

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IPO13
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIPO13, IMP13, KAP13, LGL2, RANBP13, importin 13
External IDsOMIM: 610411; MGI: 2385205; HomoloGene: 40968; GeneCards: IPO13; OMA:IPO13 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_014652

NM_146152

RefSeq (protein)

NP_055467

NP_666264

Location (UCSC)Chr 1: 43.95 – 43.97 MbChr 4: 117.75 – 117.77 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Importin-13 is a protein encoded by the IPO13 gene in humans.[5][6][7] Importin-13 is a member of the importin-β family of nuclear transport receptors (NTRs) and was first identified as a transport receptor in 2000.[8] According to PSI-blast based secondary structure PREDiction (PSIPRED), importin-13 contains 38 α-helices.[9] Importin-13 accommodates a range of cargoes due to its flexible superhelical structure and a cargo binding and release system that is distinct from other importin-like transport receptors.[8][10] IPO13 is broadly expressed in a variety of tissues in the human body, including the heart,[11] cornea,[11] fetal lung,[11] brain,[11] endometrial carcinoma,[11] and testes.[10]

Nucleocytoplasmic transport

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In eukaryotic cells, macromolecules larger than ~40 kDa are actively transported between the nuclear and cytosolic compartment through nuclear pore complexes (NPCs) via soluble transport receptors.[8][9][12] Importin-β-like factors are the largest class of NTRs and are classified as importins or exportins based on the direction of cargo transport and their response to the RanGTP gradient across the nuclear envelope.[13] Importins load their cargoes in the cytoplasm in the absence of RanGTP and release their cargoes in the nucleus upon binding RanGTP. Exportins bind their cargoes in the nucleus in the presence of RanGTP and release their cargoes in the cytoplasm upon RanGTP hydrolysis.[8][11][13] Unlike other importins, importin-13 is a versatile nuclear transport receptor with a bidirectional transport capacity, such that it mediates the nuclear import of certain cargoes and the nuclear export of other cargoes. Other nuclear transport receptors reported to facilitate both the nuclear import and export of macromolecules are exportin 5 (Msn5 in yeast) and exportin 4.[8]

The C-terminal arch of most importins is the primary binding site for cargoes. Due to its bidirectional transport capacity, different regions of importin-13 interact with cargoes to facilitate import or export. For example, ubiquitin-conjugation enzyme 9 (Ubc9) primarily interacts with the N-terminal region,[8] and characterization of crystal structures of importin-13 indicates that almost all known nuclear import cargoes bind to its N-terminal regions.[10] Low total or active concentrations of importin-13 in the nucleus show that importin-13 is a rate-limiting factor for nuclear import and export of cargo proteins.[8]

Interactions

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At least 255 importin-13 substrates have been identified. According to Baade et al., the major import cargoes of importin-13 are Ubc9, CHRAC1, and POLE3.[8] Other known importin-13 import cargoes are MAGOH,[8] NFYB,[8] DR1,[8] DRAP1,[8] RBM8,[14] paired type homeodomain transcription factors (TFs),[14] myopodinm,[14] the glucocorticoid receptor (GR),[14] RFPL3,[11] and the RBM8-MGN complex.[15] The major export cargo of importin-13 is EIF1A.[8] Other known importin-13 export cargoes include HMG20A[11] and E1F4G2.[10] Additionally, importin-13 regulates the nuclear export of the transcription factors SPI and KLF4 under conditions of oxidative stress.[12]

Several importin-13 import cargoes bind to importin-13 only as heterodimers and no interaction is observed with the monomers alone.[8] such as with the nuclear import of the NF-YB/NF-YC complex.[13] Walter et al. demonstrated that importin-13 mediates the nuclear import of the histone fold pairs CHRAC-15/17 and p12/CHRAC-17 only in the heterodimerized forms of these substrates. Furthermore, the importin-13 binding platform involves positively charged amino acids conserved between the histone fold subunits, suggesting that the binding and transportation of the heterodimers via importin-13 are driven by electrostatic interactions.[9]

Function

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Importin-13 plays an important role in the regulation of brain and lung development,[10] spermatogenesis and spermiogenesis,[10] embryonic stem cell differentiation,[16] the nuclear import of c-Jun in melanoma cells,[17] and the transcriptional response to oxidative stress.[12]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000117408Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033365Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, et al. (October 1998). "Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 5 (5): 277–286. doi:10.1093/dnares/5.5.277. PMID 9872452.
  6. ^ Mingot JM, Kostka S, Kraft R, Hartmann E, Görlich D (July 2001). "Importin 13: a novel mediator of nuclear import and export". The EMBO Journal. 20 (14): 3685–3694. doi:10.1093/emboj/20.14.3685. PMC 125545. PMID 11447110.
  7. ^ "Entrez Gene: IPO13 importin 13".
  8. ^ a b c d e f g h i j k l m n Baade I, Spillner C, Schmitt K, Valerius O, Kehlenbach RH (July 2018). "Extensive Identification and In-depth Validation of Importin 13 Cargoes". Molecular & Cellular Proteomics. 17 (7): 1337–1353. doi:10.1074/mcp.ra118.000623. PMC 6030721. PMID 29666159.
  9. ^ a b c Walker P, Doenecke D, Kahle J (April 2009). "Importin 13 mediates nuclear import of histone fold-containing chromatin accessibility complex heterodimers". The Journal of Biological Chemistry. 284 (17): 11652–11662. doi:10.1074/jbc.m806820200. PMC 2670169. PMID 19218565.
  10. ^ a b c d e f Fatima S, Wagstaff KM, Lieu KG, Davies RG, Tanaka SS, Yamaguchi YL, et al. (March 2017). "Interactome of the inhibitory isoform of the nuclear transporter Importin 13". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1864 (3): 546–561. doi:10.1016/j.bbamcr.2016.12.017. PMID 27993670.
  11. ^ a b c d e f g h Zohud BA, Guo P, Zohud BA, Li F, Hao JJ, Shan X, et al. (October 2020). "Importin 13 promotes NSCLC progression by mediating RFPL3 nuclear translocation and hTERT expression upregulation". Cell Death & Disease. 11 (10): 879. doi:10.1038/s41419-020-03101-9. PMC 7575581. PMID 33082305.
  12. ^ a b c Gajewska KA, Lescesen H, Ramialison M, Wagstaff KM, Jans DA (October 2021). "Nuclear transporter Importin-13 plays a key role in the oxidative stress transcriptional response". Nature Communications. 12 (1): 5904. Bibcode:2021NatCo..12.5904G. doi:10.1038/s41467-021-26125-x. PMC 8501021. PMID 34625540.
  13. ^ a b c Kahle J, Baake M, Doenecke D, Albig W (July 2005). "Subunits of the heterotrimeric transcription factor NF-Y are imported into the nucleus by distinct pathways involving importin beta and importin 13". Molecular and Cellular Biology. 25 (13): 5339–5354. doi:10.1128/mcb.25.13.5339-5354.2005. PMC 1157003. PMID 15964792.
  14. ^ a b c d Tao T, Lan J, Lukacs GL, Haché RJ, Kaplan F (December 2006). "Importin 13 regulates nuclear import of the glucocorticoid receptor in airway epithelial cells". American Journal of Respiratory Cell and Molecular Biology. 35 (6): 668–680. doi:10.1165/rcmb.2006-0073OC. OCLC 869605347. PMID 16809634.
  15. ^ Mingot JM, Kostka S, Kraft R, Hartmann E, Görlich D (July 2001). "Importin 13: a novel mediator of nuclear import and export". The EMBO Journal. 20 (14): 3685–3694. doi:10.1093/emboj/20.14.3685. PMC 125545. PMID 11447110.
  16. ^ Fatima S, Wagstaff KM, Lim SM, Polo JM, Young JC, Jans DA (January 2021). "The nuclear transporter importin 13 is critical for cell survival during embryonic stem cell differentiation". Biochemical and Biophysical Research Communications. 534: 141–148. doi:10.1016/j.bbrc.2020.11.099. PMID 33333437. S2CID 229316304.
  17. ^ Kappelmann-Fenzl M, Kuphal S, Krupar R, Schadendorf D, Umansky V, Vardimon L, et al. (November 2019). "Complex Formation with Monomeric α-Tubulin and Importin 13 Fosters c-Jun Protein Stability and Is Required for c-Jun's Nuclear Translocation and Activity". Cancers. 11 (11): 1806. doi:10.3390/cancers11111806. PMC 6895814. PMID 31744174.

Further reading

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