메뉴 건너뛰기




Volumn 32, Issue 6, 2013, Pages 899-913

Structural basis for the nuclear export activity of Importin13

Author keywords

eIF1A; export; Importin13; nucleo cytoplasmic transport

Indexed keywords

IMPORTIN 13; INITIATION FACTOR 1A; KARYOPHERIN; UNCLASSIFIED DRUG;

EID: 84875467016     PISSN: 02614189     EISSN: 14602075     Source Type: Journal    
DOI: 10.1038/emboj.2013.29     Document Type: Article
Times cited : (33)

References (72)
  • 2
    • 84861843696 scopus 로고    scopus 로고
    • A mechanistic overview of translation initiation in eukaryotes
    • Aitken CE, Lorsch JR (2012) A mechanistic overview of translation initiation in eukaryotes. Nat Struct Mol Biol 19: 568-576
    • (2012) Nat Struct Mol Biol , vol.19 , pp. 568-576
    • Aitken, C.E.1    Lorsch, J.R.2
  • 4
    • 0033963789 scopus 로고    scopus 로고
    • The eIF1A solution structure reveals a large RNA-binding surface important for scanning function
    • Battiste JL, Pestova TV, Hellen CU, Wagner G (2000) The eIF1A solution structure reveals a large RNA-binding surface important for scanning function. Mol Cell 5: 109-119
    • (2000) Mol Cell , vol.5 , pp. 109-119
    • Battiste, J.L.1    Pestova, T.V.2    Hellen, C.U.3    Wagner, G.4
  • 5
    • 0034616910 scopus 로고    scopus 로고
    • Structural basis for the interaction between FxFG nucleoporin repeats and importin-beta in nuclear trafficking
    • Bayliss R, Littlewood T, Stewart M (2000) Structural basis for the interaction between FxFG nucleoporin repeats and importin-beta in nuclear trafficking. Cell 102: 99-108
    • (2000) Cell , vol.102 , pp. 99-108
    • Bayliss, R.1    Littlewood, T.2    Stewart, M.3
  • 6
    • 77953672931 scopus 로고    scopus 로고
    • Conformational selection in the recognition of the snurportin importin beta binding domain by importin beta
    • Bhardwaj A, Cingolani G (2010) Conformational selection in the recognition of the snurportin importin beta binding domain by importin beta. Biochemistry 49: 5042-5047
    • (2010) Biochemistry , vol.49 , pp. 5042-5047
    • Bhardwaj, A.1    Cingolani, G.2
  • 7
    • 0345647103 scopus 로고    scopus 로고
    • RanBP1 is crucial for the release of RanGTP from importin beta-related nuclear transport factors
    • Bischoff FR, Görlich D (1997) RanBP1 is crucial for the release of RanGTP from importin beta-related nuclear transport factors. FEBS Lett 419: 249-254
    • (1997) FEBS Lett , vol.419 , pp. 249-254
    • Bischoff, F.R.1    Görlich, D.2
  • 9
    • 74749084019 scopus 로고    scopus 로고
    • Nuclear import mechanism of the EJC component Mago-Y14 revealed by structural studies of importin 13
    • Bono F, Cook AG, Grünwald M, Ebert J, Conti E (2010) Nuclear import mechanism of the EJC component Mago-Y14 revealed by structural studies of importin 13. Mol Cell 37: 211-222
    • (2010) Mol Cell , vol.37 , pp. 211-222
    • Bono, F.1    Cook, A.G.2    Grünwald, M.3    Ebert, J.4    Conti, E.5
  • 10
    • 35748960826 scopus 로고    scopus 로고
    • Conformational heterogeneity of karyopherin beta2 is segmental
    • Cansizoglu AE, Chook YM (2007) Conformational heterogeneity of karyopherin beta2 is segmental. Structure (London, England: 1993) 15: 1431-1441
    • (2007) Structure (London, England: 1993) , vol.15 , pp. 1431-1441
    • Cansizoglu, A.E.1    Chook, Y.M.2
  • 13
    • 0036923972 scopus 로고    scopus 로고
    • Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta
    • Cingolani G, Bednenko J, Gillespie MT, Gerace L (2002) Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta. Mol Cell 10: 1345-1353
    • (2002) Mol Cell , vol.10 , pp. 1345-1353
    • Cingolani, G.1    Bednenko, J.2    Gillespie, M.T.3    Gerace, L.4
  • 14
    • 0033587167 scopus 로고    scopus 로고
    • Structure of importin-beta bound to the IBB domain of importin-alpha
    • Cingolani G, Petosa C, Weis K, Mü ller CW (1999) Structure of importin-beta bound to the IBB domain of importin-alpha. Nature 399: 221-229
    • (1999) Nature , vol.399 , pp. 221-229
    • Cingolani, G.1    Petosa, C.2    Weis, K.3    Mü Ller, C.W.4
  • 15
    • 34548627531 scopus 로고    scopus 로고
    • Structural biology of nucleocytoplasmic transport
    • Cook A, Bono F, Jinek M, Conti E (2007) Structural biology of nucleocytoplasmic transport. Annu Rev Biochem 76: 647-671
    • (2007) Annu Rev Biochem , vol.76 , pp. 647-671
    • Cook, A.1    Bono, F.2    Jinek, M.3    Conti, E.4
  • 16
    • 20844458749 scopus 로고    scopus 로고
    • The structure of the nuclear export receptor Cse1 in its cytosolic state reveals a closed conformation incompatible with cargo binding
    • Cook A, Fernandez E, Lindner D, Ebert J, Schlenstedt G, Conti E (2005) The structure of the nuclear export receptor Cse1 in its cytosolic state reveals a closed conformation incompatible with cargo binding. Mol Cell 18: 355-367
    • (2005) Mol Cell , vol.18 , pp. 355-367
    • Cook, A.1    Fernandez, E.2    Lindner, D.3    Ebert, J.4    Schlenstedt, G.5    Conti, E.6
  • 17
    • 69949094998 scopus 로고    scopus 로고
    • Structures of the tRNA export factor in the nuclear and cytosolic states
    • Cook AG, Fukuhara N, Jinek M, Conti E (2009) Structures of the tRNA export factor in the nuclear and cytosolic states. Nature 461: 60-65
    • (2009) Nature , vol.461 , pp. 60-65
    • Cook, A.G.1    Fukuhara, N.2    Jinek, M.3    Conti, E.4
  • 19
    • 79959992840 scopus 로고    scopus 로고
    • Deciphering correct strategies for multiprotein complex assembly by co-expression: Application to complexes as large as the histone octamer
    • Diebold M-L, Fribourg S, Koch M, Metzger T, Romier C (2011) Deciphering correct strategies for multiprotein complex assembly by co-expression: application to complexes as large as the histone octamer. J Struct Biol 175: 178-188
    • (2011) J Struct Biol , vol.175 , pp. 178-188
    • Diebold, M.-L.1    Fribourg, S.2    Koch, M.3    Metzger, T.4    Romier, C.5
  • 20
    • 66149092358 scopus 로고    scopus 로고
    • Structural basis for assembly and disassembly of the CRM1 nuclear export complex
    • Dong X, Biswas A, Chook YM (2009a) Structural basis for assembly and disassembly of the CRM1 nuclear export complex. Nat Struct Mol Biol 16: 558-560
    • (2009) Nat Struct Mol Biol , vol.16 , pp. 558-560
    • Dong, X.1    Biswas, A.2    Chook, Y.M.3
  • 22
  • 25
    • 65649106872 scopus 로고    scopus 로고
    • Importin 13 regulates neurotransmitter release at the Drosophila neuromuscular junction
    • Giagtzoglou N, Lin YQ, Haueter C, Bellen HJ (2009) Importin 13 regulates neurotransmitter release at the Drosophila neuromuscular junction. J Neurosci 29: 5628-5639
    • (2009) J Neurosci , vol.29 , pp. 5628-5639
    • Giagtzoglou, N.1    Lin, Y.Q.2    Haueter, C.3    Bellen, H.J.4
  • 27
    • 78751629243 scopus 로고    scopus 로고
    • Structure of Importin13-Ubc9 complex: Nuclear import and release of a key regulator of sumoylation
    • Grünwald M, Bono F (2011) Structure of Importin13-Ubc9 complex: nuclear import and release of a key regulator of sumoylation. EMBO J 30: 427-438
    • (2011) EMBO J , vol.30 , pp. 427-438
    • Grünwald, M.1    Bono, F.2
  • 29
    • 0033279841 scopus 로고    scopus 로고
    • Transport between the cell nucleus and the cytoplasm
    • Görlich D, Kutay U (1999) Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol 15: 607-660
    • (1999) Annu Rev Cell Dev Biol , vol.15 , pp. 607-660
    • Görlich, D.1    Kutay, U.2
  • 31
    • 0031771756 scopus 로고    scopus 로고
    • Yeast Los1p has properties of an exportin-like nucleocytoplasmic transport factor for tRNA
    • Hellmuth K, Lau DM, Bischoff FR, Künzler M, Hurt E, Simos G (1998) Yeast Los1p has properties of an exportin-like nucleocytoplasmic transport factor for tRNA. Mol Cell Biol 18: 6374-6386
    • (1998) Mol Cell Biol , vol.18 , pp. 6374-6386
    • Hellmuth, K.1    Lau, D.M.2    Bischoff, F.R.3    Künzler, M.4    Hurt, E.5    Simos, G.6
  • 32
    • 80052742721 scopus 로고    scopus 로고
    • Molecular mechanism of scanning and start codon selection in eukaryotes
    • Hinnebusch AG (2011) Molecular mechanism of scanning and start codon selection in eukaryotes. Microbiol Mol Biol Rev 75: 434-467
    • (2011) Microbiol Mol Biol Rev , vol.75 , pp. 434-467
    • Hinnebusch, A.G.1
  • 33
    • 34948857985 scopus 로고    scopus 로고
    • Structural basis for substrate recognition and dissociation by human transportin 1
    • First page of table of contents
    • first page of table of contents Imasaki T, Shimizu T, Hashimoto H, Hidaka Y, Kose S, Imamoto N, Yamada M, Sato M (2007) Structural basis for substrate recognition and dissociation by human transportin 1. Mol Cell 28: 57-67
    • (2007) Mol Cell , vol.28 , pp. 57-67
    • Imasaki, T.1    Shimizu, T.2    Hashimoto, H.3    Hidaka, Y.4    Kose, S.5    Imamoto, N.6    Yamada, M.7    Sato, M.8
  • 34
    • 75149196287 scopus 로고    scopus 로고
    • The mechanism of eukaryotic translation initiation and principles of its regulation
    • Jackson RJ, Hellen CUT, Pestova TV (2010) The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol 11: 113-127
    • (2010) Nat Rev Mol Cell Biol , vol.11 , pp. 113-127
    • Jackson, R.J.1    Cut, H.2    Pestova, T.V.3
  • 35
    • 0027879008 scopus 로고
    • Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants
    • Kabsch W (1993) Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants. J Appl Cryst 26: 795-800
    • (1993) J Appl Cryst , vol.26 , pp. 795-800
    • Kabsch, W.1
  • 36
    • 20744448038 scopus 로고    scopus 로고
    • Subunits of the heterotrimeric transcription factor NF-Y are imported into the nucleus by distinct pathways involving importin beta and importin 13
    • Kahle J, Baake M, Doenecke D, Albig W (2005) Subunits of the heterotrimeric transcription factor NF-Y are imported into the nucleus by distinct pathways involving importin beta and importin 13. Mol Cell Biol 25: 5339-5354
    • (2005) Mol Cell Biol , vol.25 , pp. 5339-5354
    • Kahle, J.1    Baake, M.2    Doenecke, D.3    Albig, W.4
  • 37
    • 0035890258 scopus 로고    scopus 로고
    • Magoh, a human homolog of Drosophila mago nashi protein, is a component of the splicing-dependent exon-exon junction complex
    • Kataoka N, Diem MD, Kim VN, Yong J, Dreyfuss G (2001) Magoh, a human homolog of Drosophila mago nashi protein, is a component of the splicing-dependent exon-exon junction complex. EMBO J 20: 6424-6433
    • (2001) EMBO J , vol.20 , pp. 6424-6433
    • Kataoka, N.1    Diem, M.D.2    Kim, V.N.3    Yong, J.4    Dreyfuss, G.5
  • 38
    • 0033634824 scopus 로고    scopus 로고
    • Pre-mRNA splicing imprints mRNA in the nucleus with a novel RNA-binding protein that persists in the cytoplasm
    • Kataoka N, Yong J, Kim VN, Velazquez F, Perkinson RA, Wang F, Dreyfuss G (2000) Pre-mRNA splicing imprints mRNA in the nucleus with a novel RNA-binding protein that persists in the cytoplasm. Mol Cell 6: 673-682
    • (2000) Mol Cell , vol.6 , pp. 673-682
    • Kataoka, N.1    Yong, J.2    Kim, V.N.3    Velazquez, F.4    Perkinson, R.A.5    Wang, F.6    Dreyfuss, G.7
  • 39
    • 77953617671 scopus 로고    scopus 로고
    • An allosteric mechanism to displace nuclear export cargo from CRM1 and RanGTP by RanBP1
    • Koyama M, Matsuura Y (2010) An allosteric mechanism to displace nuclear export cargo from CRM1 and RanGTP by RanBP1. EMBO J 29: 2002-2013
    • (2010) EMBO J , vol.29 , pp. 2002-2013
    • Koyama, M.1    Matsuura, Y.2
  • 40
    • 0342276108 scopus 로고    scopus 로고
    • Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor
    • Kutay U, Bischoff FR, Kostka S, Kraft R, Görlich D (1997) Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell 90: 1061-1071
    • (1997) Cell , vol.90 , pp. 1061-1071
    • Kutay, U.1    Bischoff, F.R.2    Kostka, S.3    Kraft, R.4    Görlich, D.5
  • 42
    • 20444468112 scopus 로고    scopus 로고
    • Structural basis for nuclear import complex dissociation by RanGTP
    • Lee SJ, Matsuura Y, Liu SM, Stewart M (2005) Structural basis for nuclear import complex dissociation by RanGTP. Nature 435: 693-696
    • (2005) Nature , vol.435 , pp. 693-696
    • Lee, S.J.1    Matsuura, Y.2    Liu, S.M.3    Stewart, M.4
  • 47
    • 11144257756 scopus 로고    scopus 로고
    • Structural basis for the assembly of a nuclear export complex
    • Matsuura Y, Stewart M (2004) Structural basis for the assembly of a nuclear export complex. Nature 432: 872-877
    • (2004) Nature , vol.432 , pp. 872-877
    • Matsuura, Y.1    Stewart, M.2
  • 49
    • 0035898685 scopus 로고    scopus 로고
    • Importin 13: A novel mediator of nuclear import and export
    • Mingot JM, Kostka S, Kraft R, Hartmann E, Görlich D (2001) Importin 13: a novel mediator of nuclear import and export. EMBO J 20: 3685-3694
    • (2001) EMBO J , vol.20 , pp. 3685-3694
    • Mingot, J.M.1    Kostka, S.2    Kraft, R.3    Hartmann, E.4    Görlich, D.5
  • 50
    • 43149121353 scopus 로고    scopus 로고
    • Molecular basis for the recognition of snurportin 1 by importin beta
    • Mitrousis G, Olia AS, Walker-Kopp N, Cingolani G (2008) Molecular basis for the recognition of snurportin 1 by importin beta. J Biol Chem 283: 7877-7884
    • (2008) J Biol Chem , vol.283 , pp. 7877-7884
    • Mitrousis, G.1    Olia, A.S.2    Walker-Kopp, N.3    Cingolani, G.4
  • 51
    • 69849093363 scopus 로고    scopus 로고
    • Characterisation of the passive permeability barrier of nuclear pore complexes
    • Mohr D, Frey S, Fischer T, Gü ttler T, Görlich D (2009) Characterisation of the passive permeability barrier of nuclear pore complexes. EMBO J 28: 2541-2553
    • (2009) EMBO J , vol.28 , pp. 2541-2553
    • Mohr, D.1    Frey, S.2    Fischer, T.3    Gü Ttler, T.4    Görlich, D.5
  • 53
    • 37249005205 scopus 로고    scopus 로고
    • The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability
    • Niesen FH, Berglund H, Vedadi M (2007) The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat Protoc 2: 2212-2221
    • (2007) Nat Protoc , vol.2 , pp. 2212-2221
    • Niesen, F.H.1    Berglund, H.2    Vedadi, M.3
  • 57
    • 2442642835 scopus 로고    scopus 로고
    • Paired-type homeodomain transcription factors are imported into the nucleus by karyopherin 13
    • Ploski JE, Shamsher MK, Radu A (2004) Paired-type homeodomain transcription factors are imported into the nucleus by karyopherin 13. Mol Cell Biol 24: 4824-4834
    • (2004) Mol Cell Biol , vol.24 , pp. 4824-4834
    • Ploski, J.E.1    Shamsher, M.K.2    Radu, A.3
  • 58
    • 0035918226 scopus 로고    scopus 로고
    • SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting
    • Rodriguez MS, Dargemont C, Hay RT (2001) SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J Biol Chem 276: 12654-12659
    • (2001) J Biol Chem , vol.276 , pp. 12654-12659
    • Rodriguez, M.S.1    Dargemont, C.2    Hay, R.T.3
  • 59
    • 0037085459 scopus 로고    scopus 로고
    • Perturbation of SUMOlation enzyme Ubc9 by distinct domain within nucleoporin RanBP2/Nup358
    • Saitoh H, Pizzi MD, Wang J (2002) Perturbation of SUMOlation enzyme Ubc9 by distinct domain within nucleoporin RanBP2/Nup358. J Biol Chem 277: 4755-4763
    • (2002) J Biol Chem , vol.277 , pp. 4755-4763
    • Saitoh, H.1    Pizzi, M.D.2    Wang, J.3
  • 60
    • 0027136282 scopus 로고
    • Comparative protein modelling by satisfaction of spatial restraints
    • Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234: 779-815
    • (1993) J Mol Biol , vol.234 , pp. 779-815
    • Sali, A.1    Blundell, T.L.2
  • 62
    • 14844294424 scopus 로고    scopus 로고
    • Protein production by auto-induction in high density shaking cultures
    • Studier FW (2005) Protein production by auto-induction in high density shaking cultures. Protein Expr Purif 41: 207-234
    • (2005) Protein Expr Purif , vol.41 , pp. 207-234
    • Studier, F.W.1
  • 63
    • 33845382332 scopus 로고    scopus 로고
    • Importin 13 regulates nuclear import of the glucocorticoid receptor in airway epithelial cells
    • Tao T, Lan J, Lukacs GL, Haché RJG, Kaplan F (2006) Importin 13 regulates nuclear import of the glucocorticoid receptor in airway epithelial cells. Am J Respir Cell Mol Biol 35: 668-680
    • (2006) Am J Respir Cell Mol Biol , vol.35 , pp. 668-680
    • Tao, T.1    Lan, J.2    Lukacs, G.L.3    Rjg, H.4    Kaplan, F.5
  • 64
    • 0037716643 scopus 로고    scopus 로고
    • Biogenesis and nuclear export of ribosomal subunits in higher eukaryotes depend on the CRM1 export pathway
    • Thomas F, Kutay U (2003) Biogenesis and nuclear export of ribosomal subunits in higher eukaryotes depend on the CRM1 export pathway. J Cell Sci 116: 2409-2419
    • (2003) J Cell Sci , vol.116 , pp. 2409-2419
    • Thomas, F.1    Kutay, U.2
  • 65
    • 0033612390 scopus 로고    scopus 로고
    • Structural view of the Ran-Importin beta interaction at 2 3 A resolution
    • Vetter IR, Arndt A, Kutay U, Görlich D, Wittinghofer A (1999a) Structural view of the Ran-Importin beta interaction at 2.3 A resolution. Cell 97: 635-646
    • (1999) Cell , vol.97 , pp. 635-646
    • Vetter, I.R.1    Arndt, A.2    Kutay, U.3    Görlich, D.4    Wittinghofer, A.5
  • 66
    • 0033522118 scopus 로고    scopus 로고
    • Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: Implications for nuclear transport
    • Vetter IR, Nowak C, Nishimoto T, Kuhlmann J, Wittinghofer A (1999b) Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Nature 398: 39-46
    • (1999) Nature , vol.398 , pp. 39-46
    • Vetter, I.R.1    Nowak, C.2    Nishimoto, T.3    Kuhlmann, J.4    Wittinghofer, A.5
  • 67
    • 66449105245 scopus 로고    scopus 로고
    • Importin 13 mediates nuclear import of histone fold containing chrac heterodimers
    • Walker P, Doenecke D, Kahle J (2009) Importin 13 mediates nuclear import of histone fold containing chrac heterodimers. J Biol Chem 284: 11652-11662
    • (2009) J Biol Chem , vol.284 , pp. 11652-11662
    • Walker, P.1    Doenecke, D.2    Kahle, J.3
  • 68
    • 35748985252 scopus 로고    scopus 로고
    • Structural basis for RanGTP independent entry of spliceosomal U snRNPs into the nucleus
    • Wohlwend D, Strasser A, Dickmanns A, Ficner R (2007) Structural basis for RanGTP independent entry of spliceosomal U snRNPs into the nucleus. J Mol Biol 374: 1129-1138
    • (2007) J Mol Biol , vol.374 , pp. 1129-1138
    • Wohlwend, D.1    Strasser, A.2    Dickmanns, A.3    Ficner, R.4
  • 69
    • 0031079648 scopus 로고    scopus 로고
    • Leptomycin B is an inhibitor of nuclear export: Inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA
    • Wolff B, Sanglier JJ, Wang Y (1997) Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem Biol 4: 139-147
    • (1997) Chem Biol , vol.4 , pp. 139-147
    • Wolff, B.1    Sanglier, J.J.2    Wang, Y.3
  • 70
    • 78649650714 scopus 로고    scopus 로고
    • Recognition of nuclear targeting signals by Karyopherin-b proteins
    • Xu D, Farmer A, Chook YM (2010) Recognition of nuclear targeting signals by Karyopherin-b proteins. Curr Opin Struct Biol 20: 782-790
    • (2010) Curr Opin Struct Biol , vol.20 , pp. 782-790
    • Xu, D.1    Farmer, A.2    Chook, Y.M.3
  • 71
    • 0035911152 scopus 로고    scopus 로고
    • The karyopherin Kap142p/Msn5p mediates nuclear import and nuclear export of different cargo proteins
    • Yoshida K, Blobel G (2001) The karyopherin Kap142p/Msn5p mediates nuclear import and nuclear export of different cargo proteins. J Cell Biol 152: 729-740
    • (2001) J Cell Biol , vol.152 , pp. 729-740
    • Yoshida, K.1    Blobel, G.2
  • 72
    • 84864366184 scopus 로고    scopus 로고
    • Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS)
    • Zhang ZC, Chook YM (2012) Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS). Proc Natl Acad Sci USA 109: 12017-12021
    • (2012) Proc Natl Acad Sci USA , vol.109 , pp. 12017-12021
    • Zhang, Z.C.1    Chook, Y.M.2


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.