Crossref journal-article
Portland Press Ltd.
Biochemical Journal (288)
Abstract

Centaurins are a family of proteins that contain GTPase-activating protein domains, with the γ family members containing in addition a GTPase-like domain. Centaurins reside mainly in the nucleus and are known to activate phosphoinositide 3-kinase, a key regulator of cell proliferation, motility and vesicular trafficking. In the present study, using X-ray structural analysis, enzymatic assays and nucleotide-binding studies, we show that, for CENTG1 (centaurin γ-1) the GTPase-like domain has broader trinucleotide specificity. Alterations within the G4 motif of CENTG1 from the highly conserved NKXD found in typical GTPases to TQDR result in the loss of specificity, a lower affinity for the nucleotides and higher turnover rates. These results indicate that the centaurins could be more accurately classified as NTPases and point to alternative mechanisms of cell signalling control.

Bibliography

Soundararajan, M., Yang, X., Elkins, J. M., Sobott, F., & Doyle, D. A. (2007). The centaurin γ-1 GTPase-like domain functions as an NTPase. Biochemical Journal, 401(3), 679–688.

Authors 5
  1. Meera Soundararajan (first)
  2. Xiaowen Yang (additional)
  3. Jonathan M. Elkins (additional)
  4. Frank Sobott (additional)
  5. Declan A. Doyle (additional)
References 56 Referenced 26
  1. 10.1038/348125a0 / Nature / The GTPase superfamily: a conserved switch for diverse cell functions by Bourne (1990)
  2. 10.1038/349117a0 / Nature / The GTPase superfamily: conserved structure and molecular mechanism by Bourne (1991)
  3. 10.1038/366643a0 / Nature / Proteins regulating Ras and its relatives by Boguski (1993)
  4. 10.1002/j.1460-2075.1990.tb07409.x / EMBO J. / Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 Å resolution: implications for the mechanism of GTP hydrolysis by Pai (1990)
  5. 10.1126/science.2406906 / Science / Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins by Milburn (1990)
  6. 10.1038/345309a0 / Nature / Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis by Schlichting (1990)
  7. 10.1126/science.8073283 / Science / Structures of active conformations of Giα1 and the mechanism of GTP hydrolysis by Coleman (1994)
  8. 10.1038/372276a0 / Nature / GTPase mechanism of G proteins from the 1.7-Å crystal structure of transducin α-GDP–AlF4− by Sondek (1994)
  9. 10.1126/stke.2502004re13 / Science STKE / Human RAS superfamily proteins and related GTPases by Colicelli (2004)
  10. 10.1074/jbc.273.4.1859 / J. Biol. Chem. / Regulation of GRP1-catalyzed ADP ribosylation factor guanine nucleotide exchange by phosphatidylinositol 3,4,5-trisphosphate by Klarlund (1998)
  11. 10.1074/jbc.271.31.18859 / J. Biol. Chem. / Identification and cloning of centaurin-α: a novel phosphatidylinositol 3,4,5-trisphosphate-binding protein from rat brain by Hammonds-Odie (1996)
  12. 10.1016/S0092-8674(00)00195-1 / Cell / Pike: a nuclear GTPase that enhances PI3kinase activity and is regulated by protein 4.1N by Ye (2000)
  13. 10.1073/pnas.0400921101 / Proc. Natl. Acad. Sci. U.S.A. / PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt by Ahn (2004)
  14. 10.1074/jbc.273.49.32377 / J. Biol. Chem. / CREB is a regulatory target for the protein kinase Akt/PKB by Du (1998)
  15. 10.1111/j.1365-2990.2005.00660.x / Neuropathol. Appl. Neurobiol. / Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas by Knobbe (2005)
  16. 10.1038/sj.emboj.7600392 / EMBO J. / PIKE/nuclear PI 3-kinase signaling mediates the antiapoptotic actions of NGF in the nucleus by Ahn (2004)
  17. 10.1107/S090744499900846X / Acta Crystallogr. Sect. D Biol. Crystallogr. / Integration of macromolecular diffraction data by Leslie (1999)
  18. 10.1107/S0907444994003112 / Acta Crystallogr. Sect. D Biol. Crystallogr. / The CCP4 suite: programs for protein crystallography by Collaborative Computational Project Number 4 (1994)
  19. 10.1107/S0907444903028956 / Acta Crystallogr. Sect. D Biol. Crystallogr. / Likelihood-enhanced fast rotation functions by Storoni (2004)
  20. 10.1107/S0108767390010224 / Acta Crystallogr. Sect. A Found. Crystallogr. / Improved methods for building protein models in electron density maps and the location of errors in these models by Jones (1991)
  21. 10.1107/S0907444998003254 / Acta Crystallogr. Sect. D Biol. Crystallogr. / Crystallography & NMR system: a new software suite for macromolecular structure determination by Brunger (1998)
  22. 10.1107/S090744499801405X / Acta Crystallogr. Sect. D Biol. Crystallogr. / Efficient anisotropic refinement of macromolecular structures using FFT by Murshudov (1999)
  23. 10.1016/S0959-440X(02)00400-1 / Curr. Opin. Struct. Biol. / Protein complexes gain momentum by Sobott (2002)
  24. 10.1021/ac034251c / Anal. Chem. / Use of a microchip device coupled with mass spectrometry for ligand screening of a multi-protein target by Keetch (2003)
  25. 10.1074/jbc.273.19.11596 / J. Biol. Chem. / Determination of interaction sites on the small G protein RhoA for phospholipase D by Bae (1998)
  26. 10.1074/jbc.270.7.2901 / J. Biol. Chem. / Quantitative analysis of the complex between p21ras and the Ras-binding domain of the human Raf-1 protein kinase by Herrmann (1995)
  27. 10.1073/pnas.081441398 / Proc. Natl. Acad. Sci. U.S.A. / Dynamic properties of the Ras switch I region and its importance for binding to effectors by Spoerner (2001)
  28. 10.1038/341209a0 / Nature / Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation by Pai (1989)
  29. 10.1021/bi00016a028 / Biochemistry / Interactions between the amino- and carboxyl-terminal regions of Gα subunits: analysis of mutated Gαo/Gαi2 chimeras by Denker (1995)
  30. {'key': '2021112213082167200_B30', 'first-page': '87', 'article-title': 'Biochemical and biological consequences of changing the specificity of p21ras from guanosine to xanthosine nucleotides', 'volume': '12', 'author': 'Schmidt', 'year': '1996', 'journal-title': 'Oncogene'} / Oncogene / Biochemical and biological consequences of changing the specificity of p21ras from guanosine to xanthosine nucleotides by Schmidt (1996)
  31. 10.1021/bi00201a019 / Biochemistry / Elongation factor Tu D138N, a mutant with modified substrate specificity, as a tool to study energy consumption in protein biosynthesis by Weijland (1994)
  32. 10.1128/MCB.19.9.6297 / Mol. Cell. Biol. / The Ras mutant D119N is both dominant negative and activated by Cool (1999)
  33. 10.1073/pnas.83.4.952 / Proc. Natl. Acad. Sci. U.S.A. / Mutant ras-encoded proteins with altered nucleotide binding exert dominant biological effects by Sigal (1986)
  34. 10.1074/jbc.270.17.10002 / J. Biol. Chem. / Switching nucleotide specificity of Ha-Ras p21 by a single amino acid substitution at aspartate 119 by Zhong (1995)
  35. 10.1126/science.277.5324.333 / Science / The Ras–RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants by Scheffzek (1997)
  36. 10.1038/4156 / Nat. Struct. Biol. / Structures of Cdc42 bound to the active and catalytically compromised forms of Cdc42GAP by Nassar (1998)
  37. 10.1038/41805 / Nature / Crystal structure of a small G protein in complex with the GTPase-activating protein rhoGAP by Rittinger (1997)
  38. 10.1038/39651 / Nature / Structure at 1.65 Å of RhoA and its GTPase-activating protein in complex with a transition-state analogue by Rittinger (1997)
  39. 10.1074/jbc.M301381200 / J. Biol. Chem. / The GTPase activity and C-terminal cysteine of the Escherichia coli MnmE protein are essential for its tRNA modifying function by Yim (2003)
  40. 10.1016/S0021-9258(18)51599-4 / J. Biol. Chem. / C-terminal truncation of p21H preserves crucial kinetic and structural properties by John (1989)
  41. 10.1074/jbc.270.10.5048 / J. Biol. Chem. / Biochemical and functional characterization of a recombinant GTPase, Rab5, and two of its mutants by Hoffenberg (1995)
  42. 10.1128/MCB.23.7.2476-2488.2003 / Mol. Cell. Biol. / GGAPs, a new family of bifunctional GTP-binding and GTPase-activating proteins by Xia (2003)
  43. 10.1074/jbc.M202969200 / J. Biol. Chem. / AGAP1, an endosome-associated, phosphoinositide-dependent ADP-ribosylation factor GTPase-activating protein that affects actin cytoskeleton by Nie (2002)
  44. 10.1016/S0021-9258(17)42232-0 / J. Biol. Chem. / Characterization of rhoGAP. A GTPase-activating protein for rho-related small GTPases by Lancaster (1994)
  45. 10.1016/0168-9525(94)90114-7 / Trends Genet. / GAPs for rho-related GTPases by Lamarche (1994)
  46. 10.1016/S0968-0896(97)00021-7 / Bioorg. Med. Chem. / Detection and structural characterization of ras oncoprotein-inhibitors complexes by electrospray mass spectrometry by Ganguly (1997)
  47. 10.1016/S1367-5931(99)00008-3 / Curr. Opin. Chem. Biol. / Thermodynamic analysis of biomolecular interactions by Cooper (1999)
  48. 10.1021/bi00477a025 / Biochemistry / Kinetics of interaction of nucleotides with nucleotide-free H-ras p21 by John (1990)
  49. 10.1016/S0955-0674(00)00236-2 / Curr. Opin. Cell Biol. / Dynamin family of mechanoenzymes by Danino (2001)
  50. 10.1074/jbc.M407007200 / J. Biol. Chem. / Dynamin GTPase domain mutants that differentially affect GTP binding, GTP hydrolysis, and clathrin-mediated endocytosis by Song (2004)
  51. 10.1021/bi000033r / Biochemistry / The mechanism of GTP hydrolysis by dynamin II: a transient kinetic study by Binns (2000)
  52. 10.1016/S0021-9258(19)77694-7 / J. Biol. Chem. / Kinetic analysis of the hydrolysis of GTP by p21N-ras: the basal GTPase mechanism by Neal (1988)
  53. 10.1093/emboj/18.24.7063 / EMBO J. / The Escherichia coli trmE (mnmE) gene, involved in tRNA modification, codes for an evolutionarily conserved GTPase with unusual biochemical properties by Cabedo (1999)
  54. 10.1006/jmbi.1998.2197 / J. Mol. Biol. / Aminoacylation of hypomodified tRNAGlu in vivo by Kruger (1998)
  55. 10.1038/415541a / Nature / Phospholipase Cγ1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE by Ye (2002)
  56. 10.1016/S0968-0004(99)01429-2 / Trends Biochem. Sci. / GEFs: structural basis for their activation of small GTP-binding proteins by Cherfils (1999)
Dates
Type When
Created 18 years, 5 months ago (March 15, 2007, 5:12 a.m.)
Deposited 3 years, 9 months ago (Nov. 22, 2021, 8:19 a.m.)
Indexed 1 year ago (Aug. 11, 2024, 12:28 p.m.)
Issued 18 years, 7 months ago (Jan. 12, 2007)
Published 18 years, 7 months ago (Jan. 12, 2007)
Published Online 18 years, 7 months ago (Jan. 12, 2007)
Published Print 18 years, 6 months ago (Feb. 1, 2007)
Funders 0

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@article{Soundararajan_2007, title={The centaurin γ-1 GTPase-like domain functions as an NTPase}, volume={401}, ISSN={1470-8728}, url={http://dx.doi.org/10.1042/bj20060555}, DOI={10.1042/bj20060555}, number={3}, journal={Biochemical Journal}, publisher={Portland Press Ltd.}, author={Soundararajan, Meera and Yang, Xiaowen and Elkins, Jonathan M. and Sobott, Frank and Doyle, Declan A.}, year={2007}, month=jan, pages={679–688} }