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. 1995 Feb 28;92(5):1749–1753. doi: 10.1073/pnas.92.5.1749

Human RanGTPase-activating protein RanGAP1 is a homologue of yeast Rna1p involved in mRNA processing and transport.

F R Bischoff 1, H Krebber 1, T Kempf 1, I Hermes 1, H Ponstingl 1
PMCID: PMC42597  PMID: 7878053

Abstract

RanGAP1 is the GTPase activator for the nuclear Ras-related regulatory protein Ran, converting it to the putatively inactive GDP-bound state. Here, we report the amino acid sequence of RanGAP1, derived from cDNA and peptide sequences. We found it to be homologous to murine Fug1, implicated in early embryonic development, and to Rna1p from Saccharomyces cerevisiae and Schizosaccharomyces pombe. Mutations of budding yeast RNA1 are known to result in defects in RNA processing and nucleocytoplasmic mRNA transport. Concurrently, we have isolated Rna1p as the major RanGAP activity from Sc. pombe. Both this protein and recombinant Rna1p were found to stimulate RanGTPase activity to an extent almost identical to that of human RanGAP1, indicating the functional significance of the sequence homology. The Ran-specific guanine nucleotide exchange factor RCC1 and its yeast homologues are restricted to the nucleus, while Rna1p is reported to be localized to the cytoplasm. We suggest a model in which both activities, nuclear GDP-to-GTP exchange on Ran and cytoplasmic hydrolysis of Ran-bound GTP, are essential for shuttling of Ran between the two cellular compartments. Thus, a defect in either of the two antagonistic regulators of Ran would result in a shutdown of Ran-dependent transport processes, in agreement with the almost identical phenotypes described for such defects in budding yeast.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atkinson N. S., Dunst R. W., Hopper A. K. Characterization of an essential Saccharomyces cerevisiae gene related to RNA processing: cloning of RNA1 and generation of a new allele with a novel phenotype. Mol Cell Biol. 1985 May;5(5):907–915. doi: 10.1128/mcb.5.5.907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Belhumeur P., Lee A., Tam R., DiPaolo T., Fortin N., Clark M. W. GSP1 and GSP2, genetic suppressors of the prp20-1 mutant in Saccharomyces cerevisiae: GTP-binding proteins involved in the maintenance of nuclear organization. Mol Cell Biol. 1993 Apr;13(4):2152–2161. doi: 10.1128/mcb.13.4.2152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bischoff F. R., Klebe C., Kretschmer J., Wittinghofer A., Ponstingl H. RanGAP1 induces GTPase activity of nuclear Ras-related Ran. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2587–2591. doi: 10.1073/pnas.91.7.2587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bischoff F. R., Ponstingl H. Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature. 1991 Nov 7;354(6348):80–82. doi: 10.1038/354080a0. [DOI] [PubMed] [Google Scholar]
  5. Bischoff F. R., Ponstingl H. Mitotic regulator protein RCC1 is complexed with a nuclear ras-related polypeptide. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10830–10834. doi: 10.1073/pnas.88.23.10830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clark K. L., Sprague G. F., Jr Yeast pheromone response pathway: characterization of a suppressor that restores mating to receptorless mutants. Mol Cell Biol. 1989 Jun;9(6):2682–2694. doi: 10.1128/mcb.9.6.2682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coutavas E., Ren M., Oppenheim J. D., D'Eustachio P., Rush M. G. Characterization of proteins that interact with the cell-cycle regulatory protein Ran/TC4. Nature. 1993 Dec 9;366(6455):585–587. doi: 10.1038/366585a0. [DOI] [PubMed] [Google Scholar]
  9. DeGregori J., Russ A., von Melchner H., Rayburn H., Priyaranjan P., Jenkins N. A., Copeland N. G., Ruley H. E. A murine homolog of the yeast RNA1 gene is required for postimplantation development. Genes Dev. 1994 Feb 1;8(3):265–276. doi: 10.1101/gad.8.3.265. [DOI] [PubMed] [Google Scholar]
  10. Fleischmann M., Clark M. W., Forrester W., Wickens M., Nishimoto T., Aebi M. Analysis of yeast prp20 mutations and functional complementation by the human homologue RCC1, a protein involved in the control of chromosome condensation. Mol Gen Genet. 1991 Jul;227(3):417–423. doi: 10.1007/BF00273932. [DOI] [PubMed] [Google Scholar]
  11. Forrester W., Stutz F., Rosbash M., Wickens M. Defects in mRNA 3'-end formation, transcription initiation, and mRNA transport associated with the yeast mutation prp20: possible coupling of mRNA processing and chromatin structure. Genes Dev. 1992 Oct;6(10):1914–1926. doi: 10.1101/gad.6.10.1914. [DOI] [PubMed] [Google Scholar]
  12. Frasch M. The maternally expressed Drosophila gene encoding the chromatin-binding protein BJ1 is a homolog of the vertebrate gene Regulator of Chromatin Condensation, RCC1. EMBO J. 1991 May;10(5):1225–1236. doi: 10.1002/j.1460-2075.1991.tb08064.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hopper A. K., Traglia H. M., Dunst R. W. The yeast RNA1 gene product necessary for RNA processing is located in the cytosol and apparently excluded from the nucleus. J Cell Biol. 1990 Aug;111(2):309–321. doi: 10.1083/jcb.111.2.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kadowaki T., Goldfarb D., Spitz L. M., Tartakoff A. M., Ohno M. Regulation of RNA processing and transport by a nuclear guanine nucleotide release protein and members of the Ras superfamily. EMBO J. 1993 Jul;12(7):2929–2937. doi: 10.1002/j.1460-2075.1993.tb05955.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kornbluth S., Dasso M., Newport J. Evidence for a dual role for TC4 protein in regulating nuclear structure and cell cycle progression. J Cell Biol. 1994 May;125(4):705–719. doi: 10.1083/jcb.125.4.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lounsbury K. M., Beddow A. L., Macara I. G. A family of proteins that stabilize the Ran/TC4 GTPase in its GTP-bound conformation. J Biol Chem. 1994 Apr 15;269(15):11285–11290. [PubMed] [Google Scholar]
  17. Matsumoto T., Beach D. Premature initiation of mitosis in yeast lacking RCC1 or an interacting GTPase. Cell. 1991 Jul 26;66(2):347–360. doi: 10.1016/0092-8674(91)90624-8. [DOI] [PubMed] [Google Scholar]
  18. Melchior F., Paschal B., Evans J., Gerace L. Inhibition of nuclear protein import by nonhydrolyzable analogues of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor. J Cell Biol. 1993 Dec;123(6 Pt 2):1649–1659. doi: 10.1083/jcb.123.6.1649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Melchior F., Weber K., Gerke V. A functional homologue of the RNA1 gene product in Schizosaccharomyces pombe: purification, biochemical characterization, and identification of a leucine-rich repeat motif. Mol Biol Cell. 1993 Jun;4(6):569–581. doi: 10.1091/mbc.4.6.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Moore M. S., Blobel G. The GTP-binding protein Ran/TC4 is required for protein import into the nucleus. Nature. 1993 Oct 14;365(6447):661–663. doi: 10.1038/365661a0. [DOI] [PubMed] [Google Scholar]
  21. Nishimoto T., Eilen E., Basilico C. Premature of chromosome condensation in a ts DNA- mutant of BHK cells. Cell. 1978 Oct;15(2):475–483. doi: 10.1016/0092-8674(78)90017-x. [DOI] [PubMed] [Google Scholar]
  22. Ohtsubo M., Okazaki H., Nishimoto T. The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA. J Cell Biol. 1989 Oct;109(4 Pt 1):1389–1397. doi: 10.1083/jcb.109.4.1389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ohtsubo M., Yoshida T., Seino H., Nishitani H., Clark K. L., Sprague G. F., Jr, Frasch M., Nishimoto T. Mutation of the hamster cell cycle gene RCC1 is complemented by the homologous genes of Drosophila and S.cerevisiae. EMBO J. 1991 May;10(5):1265–1273. doi: 10.1002/j.1460-2075.1991.tb08068.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ren M., Coutavas E., D'Eustachio P., Rush M. G. Effects of mutant Ran/TC4 proteins on cell cycle progression. Mol Cell Biol. 1994 Jun;14(6):4216–4224. doi: 10.1128/mcb.14.6.4216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ren M., Drivas G., D'Eustachio P., Rush M. G. Ran/TC4: a small nuclear GTP-binding protein that regulates DNA synthesis. J Cell Biol. 1993 Jan;120(2):313–323. doi: 10.1083/jcb.120.2.313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sazer S., Nurse P. A fission yeast RCC1-related protein is required for the mitosis to interphase transition. EMBO J. 1994 Feb 1;13(3):606–615. doi: 10.1002/j.1460-2075.1994.tb06298.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Traglia H. M., Atkinson N. S., Hopper A. K. Structural and functional analyses of Saccharomyces cerevisiae wild-type and mutant RNA1 genes. Mol Cell Biol. 1989 Jul;9(7):2989–2999. doi: 10.1128/mcb.9.7.2989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Vijayraghavan U., Company M., Abelson J. Isolation and characterization of pre-mRNA splicing mutants of Saccharomyces cerevisiae. Genes Dev. 1989 Aug;3(8):1206–1216. doi: 10.1101/gad.3.8.1206. [DOI] [PubMed] [Google Scholar]

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