| Structural highlights
Function
[XPO5_HUMAN] Mediates the nuclear export of proteins bearing a double-stranded RNA binding domain (dsRBD) and double-stranded RNAs (cargos). XPO5 in the nucleus binds cooperatively to the RNA and to the GTPase Ran in its active GTP-bound form. Proteins containing dsRBDs can associate with this trimeric complex through the RNA. Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause disassembly of the complex and release of the cargo from the export receptor. XPO5 then returns to the nuclear compartment by diffusion through the nuclear pore complex, to mediate another round of transport. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Overexpression may in some circumstances enhance RNA-mediated gene silencing (RNAi). Mediates nuclear export of isoform 5 of ADAR/ADAR1 in a RanGTP-dependent manner.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Mediates the nuclear export of micro-RNA precursors, which form short hairpins. Also mediates the nuclear export of synthetic short hairpin RNAs used for RNA interference, and adenovirus VA1 dsRNA. In some circumstances can also mediate the nuclear export of deacylated and aminoacylated tRNAs. Specifically recognizes dsRNAs that lack a 5'-overhang in a sequence-independent manner, have only a short 3'-overhang, and that have a double-stranded length of at least 15 base-pairs. Binding is dependent on Ran-GTP.[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [RAN_CANLF] GTPase involved in nucleocytoplasmic transport, participating both to the import and the export from the nucleus of proteins and RNAs. Switches between a cytoplasmic GDP- and a nuclear GTP-bound state by nucleotide exchange and GTP hydrolysis. Nuclear import receptors such as importin beta bind their substrates only in the absence of GTP-bound RAN and release them upon direct interaction with GTP-bound RAN, while export receptors behave in the opposite way. Thereby, RAN controls cargo loading and release by transport receptors in the proper compartment and ensures the directionality of the transport. Interaction with RANBP1 induces a conformation change in the complex formed by XPO1 and RAN that triggers the release of the nuclear export signal of cargo proteins. RAN (GTP-bound form) triggers microtubule assembly at mitotic chromosomes and is required for normal mitotic spindle assembly and chromosome segregation. Required for normal progress through mitosis. The complex with BIRC5/survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules. Acts as a negative regulator of the kinase activity of VRK1 and VRK2. Enhances AR-mediated transactivation.[UniProtKB:P62826]
Publication Abstract from PubMed
In the nucleus, RanGTP binding to importin dissociates the cargo. On the other hand, RanGTP enables exportin to bind export cargo and form the export complex by each exportin's own cargo selection mechanism. Here, we present two X-ray structures for Exportin-5 (Exp-5) alone and Exp-5:RanGTP intermediate complex. The structure of Exp-5 adopts a ring-shaped closed conformation by C-terminal anchor residues 1,167-1,179, interacting with N-terminal heat repeats 4-9. The closed form of Exp-5 is important for the stability of the cargo-free state. Interaction between Exp-5 and RanGTP induces elimination of intramolecular contacts of the C-terminal anchor. A large movement of N-terminal 1-9th heat repeats and C-terminal 19-20th heat repeats creates an open space for RanGTP accommodation. Exp-5 in Exp-5:RanGTP and Exp-5:RanGTP:pre-miRNA adopts the same conformation. RanGTP binding to Exp-5 creates a selective molecular cage area for accepting its cargoes, such as small double-stranded RNAs, without conformational change in Exp-5:RanGTP.
Structural Basis for Selective Binding of Export Cargoes by Exportin-5.,Yamazawa R, Jiko C, Choi S, Park IY, Nakagawa A, Yamashita E, Lee SJ Structure. 2018 Jul 16. pii: S0969-2126(18)30246-6. doi:, 10.1016/j.str.2018.06.014. PMID:30100359[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bohnsack MT, Regener K, Schwappach B, Saffrich R, Paraskeva E, Hartmann E, Gorlich D. Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport pathways to confine translation to the cytoplasm. EMBO J. 2002 Nov 15;21(22):6205-15. PMID:12426392
- ↑ Brownawell AM, Macara IG. Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins. J Cell Biol. 2002 Jan 7;156(1):53-64. Epub 2002 Jan 3. PMID:11777942 doi:http://dx.doi.org/10.1083/jcb.200110082
- ↑ Calado A, Treichel N, Muller EC, Otto A, Kutay U. Exportin-5-mediated nuclear export of eukaryotic elongation factor 1A and tRNA. EMBO J. 2002 Nov 15;21(22):6216-24. PMID:12426393
- ↑ Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003 Dec 15;17(24):3011-6. Epub 2003 Dec 17. PMID:14681208 doi:http://dx.doi.org/10.1101/gad.1158803
- ↑ Gwizdek C, Ossareh-Nazari B, Brownawell AM, Doglio A, Bertrand E, Macara IG, Dargemont C. Exportin-5 mediates nuclear export of minihelix-containing RNAs. J Biol Chem. 2003 Feb 21;278(8):5505-8. Epub 2002 Dec 30. PMID:12509441 doi:http://dx.doi.org/10.1074/jbc.C200668200
- ↑ Gwizdek C, Ossareh-Nazari B, Brownawell AM, Evers S, Macara IG, Dargemont C. Minihelix-containing RNAs mediate exportin-5-dependent nuclear export of the double-stranded RNA-binding protein ILF3. J Biol Chem. 2004 Jan 9;279(2):884-91. Epub 2003 Oct 21. PMID:14570900 doi:http://dx.doi.org/10.1074/jbc.M306808200
- ↑ Chen T, Brownawell AM, Macara IG. Nucleocytoplasmic shuttling of JAZ, a new cargo protein for exportin-5. Mol Cell Biol. 2004 Aug;24(15):6608-19. PMID:15254228 doi:http://dx.doi.org/10.1128/MCB.24.15.6608-6619.2004
- ↑ Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA. 2004 Feb;10(2):185-91. PMID:14730017
- ↑ Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U. Nuclear export of microRNA precursors. Science. 2004 Jan 2;303(5654):95-8. Epub 2003 Nov 20. PMID:14631048 doi:http://dx.doi.org/10.1126/science.1090599
- ↑ Yi R, Doehle BP, Qin Y, Macara IG, Cullen BR. Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs. RNA. 2005 Feb;11(2):220-6. Epub 2004 Dec 21. PMID:15613540 doi:http://dx.doi.org/10.1261/rna.7233305
- ↑ Fritz J, Strehblow A, Taschner A, Schopoff S, Pasierbek P, Jantsch MF. RNA-regulated interaction of transportin-1 and exportin-5 with the double-stranded RNA-binding domain regulates nucleocytoplasmic shuttling of ADAR1. Mol Cell Biol. 2009 Mar;29(6):1487-97. doi: 10.1128/MCB.01519-08. Epub 2009 Jan, 5. PMID:19124606 doi:10.1128/MCB.01519-08
- ↑ Bohnsack MT, Regener K, Schwappach B, Saffrich R, Paraskeva E, Hartmann E, Gorlich D. Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport pathways to confine translation to the cytoplasm. EMBO J. 2002 Nov 15;21(22):6205-15. PMID:12426392
- ↑ Brownawell AM, Macara IG. Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins. J Cell Biol. 2002 Jan 7;156(1):53-64. Epub 2002 Jan 3. PMID:11777942 doi:http://dx.doi.org/10.1083/jcb.200110082
- ↑ Calado A, Treichel N, Muller EC, Otto A, Kutay U. Exportin-5-mediated nuclear export of eukaryotic elongation factor 1A and tRNA. EMBO J. 2002 Nov 15;21(22):6216-24. PMID:12426393
- ↑ Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003 Dec 15;17(24):3011-6. Epub 2003 Dec 17. PMID:14681208 doi:http://dx.doi.org/10.1101/gad.1158803
- ↑ Gwizdek C, Ossareh-Nazari B, Brownawell AM, Doglio A, Bertrand E, Macara IG, Dargemont C. Exportin-5 mediates nuclear export of minihelix-containing RNAs. J Biol Chem. 2003 Feb 21;278(8):5505-8. Epub 2002 Dec 30. PMID:12509441 doi:http://dx.doi.org/10.1074/jbc.C200668200
- ↑ Gwizdek C, Ossareh-Nazari B, Brownawell AM, Evers S, Macara IG, Dargemont C. Minihelix-containing RNAs mediate exportin-5-dependent nuclear export of the double-stranded RNA-binding protein ILF3. J Biol Chem. 2004 Jan 9;279(2):884-91. Epub 2003 Oct 21. PMID:14570900 doi:http://dx.doi.org/10.1074/jbc.M306808200
- ↑ Chen T, Brownawell AM, Macara IG. Nucleocytoplasmic shuttling of JAZ, a new cargo protein for exportin-5. Mol Cell Biol. 2004 Aug;24(15):6608-19. PMID:15254228 doi:http://dx.doi.org/10.1128/MCB.24.15.6608-6619.2004
- ↑ Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA. 2004 Feb;10(2):185-91. PMID:14730017
- ↑ Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U. Nuclear export of microRNA precursors. Science. 2004 Jan 2;303(5654):95-8. Epub 2003 Nov 20. PMID:14631048 doi:http://dx.doi.org/10.1126/science.1090599
- ↑ Yi R, Doehle BP, Qin Y, Macara IG, Cullen BR. Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs. RNA. 2005 Feb;11(2):220-6. Epub 2004 Dec 21. PMID:15613540 doi:http://dx.doi.org/10.1261/rna.7233305
- ↑ Fritz J, Strehblow A, Taschner A, Schopoff S, Pasierbek P, Jantsch MF. RNA-regulated interaction of transportin-1 and exportin-5 with the double-stranded RNA-binding domain regulates nucleocytoplasmic shuttling of ADAR1. Mol Cell Biol. 2009 Mar;29(6):1487-97. doi: 10.1128/MCB.01519-08. Epub 2009 Jan, 5. PMID:19124606 doi:10.1128/MCB.01519-08
- ↑ Yamazawa R, Jiko C, Choi S, Park IY, Nakagawa A, Yamashita E, Lee SJ. Structural Basis for Selective Binding of Export Cargoes by Exportin-5. Structure. 2018 Jul 16. pii: S0969-2126(18)30246-6. doi:, 10.1016/j.str.2018.06.014. PMID:30100359 doi:http://dx.doi.org/10.1016/j.str.2018.06.014
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