4af3

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Human Aurora B Kinase in complex with INCENP and VX-680Human Aurora B Kinase in complex with INCENP and VX-680

Structural highlights

4af3 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.75Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AURKB_HUMAN Disruptive regulation of expression is a possible mechanism of the perturbation of chromosomal integrity in cancer cells through its dominant-negative effect on cytokinesis.

Function

AURKB_HUMAN Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis. Required for central/midzone spindle assembly and cleavage furrow formation. AURKB phosphorylates the CPC complex subunits BIRC5/survivin, CDCA8/borealin and INCENP. Phosphorylation of INCENP leads to increased AURKB activity. Other known AURKB substrates involved in centromeric functions and mitosis are CENPA, DES/desmin, GPAF, KIF2C, NSUN2, RACGAP1, SEPT1, VIM/vimentin, GSG2/Haspin, and histone H3. A positive feedback loop involving GSG2 and AURKB contributes to localization of CPC to centromeres. Phosphorylation of VIM controls vimentin filament segregation in cytokinetic process, whereas histone H3 is phosphorylated at 'Ser-10' and 'Ser-28' during mitosis (H3S10ph and H3S28ph, respectively). A positive feedback between GSG2 and AURKB contributes to CPC localization. AURKB is also required for kinetochore localization of BUB1 and SGOL1. Phosphorylation of p53/TP53 negatively regulates its transcriptional activity. Key regulator of active promoters in resting B- and T-lymphocytes: acts by mediating phosphorylation of H3S28ph at active promoters in resting B-cells, inhibiting RNF2/RING1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

Publication Abstract from PubMed

We present the structure of the human Aurora B kinase domain in complex with the C-terminal Aurora-binding region of human INCENP and the Aurora kinase inhibitor VX-680. The structure unexpectedly reveals a dimeric arrangement of the Aurora B:INCENP complex, which was confirmed to exist in solution by analytical ultracentrifugation. The dimerization involves a domain swap of the activation loop, resulting in a different conformation of the DFG motif as compared to that seen in other kinase complexes with VX-680. The binding of INCENP differs significantly from that seen in the Xenopus laevis Aurora B:INCENP complex currently used as a model for structure-based design for this important oncology target.

Crystal Structure of Human Aurora B in Complex with INCENP and VX-680.,Elkins JM, Santaguida S, Musacchio A, Knapp S J Med Chem. 2012 Sep 13;55(17):7841-8. Epub 2012 Sep 4. PMID:22920039[18]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Wheatley SP, Carvalho A, Vagnarelli P, Earnshaw WC. INCENP is required for proper targeting of Survivin to the centromeres and the anaphase spindle during mitosis. Curr Biol. 2001 Jun 5;11(11):886-90. PMID:11516652
  2. ↑ Zeitlin SG, Shelby RD, Sullivan KF. CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis. J Cell Biol. 2001 Dec 24;155(7):1147-57. Epub 2001 Dec 24. PMID:11756469 doi:http://dx.doi.org/10.1083/jcb.200108125
  3. ↑ Goto H, Yasui Y, Nigg EA, Inagaki M. Aurora-B phosphorylates Histone H3 at serine28 with regard to the mitotic chromosome condensation. Genes Cells. 2002 Jan;7(1):11-7. PMID:11856369
  4. ↑ Crosio C, Fimia GM, Loury R, Kimura M, Okano Y, Zhou H, Sen S, Allis CD, Sassone-Corsi P. Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol Cell Biol. 2002 Feb;22(3):874-85. PMID:11784863
  5. ↑ Minoshima Y, Kawashima T, Hirose K, Tonozuka Y, Kawajiri A, Bao YC, Deng X, Tatsuka M, Narumiya S, May WS Jr, Nosaka T, Semba K, Inoue T, Satoh T, Inagaki M, Kitamura T. Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis. Dev Cell. 2003 Apr;4(4):549-60. PMID:12689593
  6. ↑ Goto H, Yasui Y, Kawajiri A, Nigg EA, Terada Y, Tatsuka M, Nagata K, Inagaki M. Aurora-B regulates the cleavage furrow-specific vimentin phosphorylation in the cytokinetic process. J Biol Chem. 2003 Mar 7;278(10):8526-30. Epub 2002 Nov 27. PMID:12458200 doi:http://dx.doi.org/10.1074/jbc.M210892200
  7. ↑ Kawajiri A, Yasui Y, Goto H, Tatsuka M, Takahashi M, Nagata K, Inagaki M. Functional significance of the specific sites phosphorylated in desmin at cleavage furrow: Aurora-B may phosphorylate and regulate type III intermediate filaments during cytokinesis coordinatedly with Rho-kinase. Mol Biol Cell. 2003 Apr;14(4):1489-500. PMID:12686604 doi:http://dx.doi.org/10.1091/mbc.E02-09-0612
  8. ↑ Honda R, Korner R, Nigg EA. Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis. Mol Biol Cell. 2003 Aug;14(8):3325-41. Epub 2003 May 29. PMID:12925766 doi:http://dx.doi.org/10.1091/mbc.E02-11-0769
  9. ↑ Wheatley SP, Henzing AJ, Dodson H, Khaled W, Earnshaw WC. Aurora-B phosphorylation in vitro identifies a residue of survivin that is essential for its localization and binding to inner centromere protein (INCENP) in vivo. J Biol Chem. 2004 Feb 13;279(7):5655-60. Epub 2003 Nov 10. PMID:14610074 doi:http://dx.doi.org/10.1074/jbc.M311299200
  10. ↑ Yasui Y, Urano T, Kawajiri A, Nagata K, Tatsuka M, Saya H, Furukawa K, Takahashi T, Izawa I, Inagaki M. Autophosphorylation of a newly identified site of Aurora-B is indispensable for cytokinesis. J Biol Chem. 2004 Mar 26;279(13):12997-3003. Epub 2004 Jan 13. PMID:14722118 doi:http://dx.doi.org/10.1074/jbc.M311128200
  11. ↑ Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS. Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci. 2004 Mar 15;117(Pt 8):1577-89. PMID:15020684 doi:http://dx.doi.org/10.1242/jcs.01006
  12. ↑ Gassmann R, Carvalho A, Henzing AJ, Ruchaud S, Hudson DF, Honda R, Nigg EA, Gerloff DL, Earnshaw WC. Borealin: a novel chromosomal passenger required for stability of the bipolar mitotic spindle. J Cell Biol. 2004 Jul 19;166(2):179-91. Epub 2004 Jul 12. PMID:15249581 doi:http://dx.doi.org/10.1083/jcb.200404001
  13. ↑ Tien AC, Lin MH, Su LJ, Hong YR, Cheng TS, Lee YC, Lin WJ, Still IH, Huang CY. Identification of the substrates and interaction proteins of aurora kinases from a protein-protein interaction model. Mol Cell Proteomics. 2004 Jan;3(1):93-104. Epub 2003 Nov 5. PMID:14602875 doi:http://dx.doi.org/10.1074/mcp.M300072-MCP200
  14. ↑ Yuce O, Piekny A, Glotzer M. An ECT2-centralspindlin complex regulates the localization and function of RhoA. J Cell Biol. 2005 Aug 15;170(4):571-82. PMID:16103226 doi:10.1083/jcb.200501097
  15. ↑ Pouwels J, Kukkonen AM, Lan W, Daum JR, Gorbsky GJ, Stukenberg T, Kallio MJ. Shugoshin 1 plays a central role in kinetochore assembly and is required for kinetochore targeting of Plk1. Cell Cycle. 2007 Jul 1;6(13):1579-85. Epub 2007 May 16. PMID:17617734
  16. ↑ Wang F, Ulyanova NP, van der Waal MS, Patnaik D, Lens SM, Higgins JM. A positive feedback loop involving Haspin and Aurora B promotes CPC accumulation at centromeres in mitosis. Curr Biol. 2011 Jun 21;21(12):1061-9. doi: 10.1016/j.cub.2011.05.016. Epub 2011, Jun 9. PMID:21658950 doi:http://dx.doi.org/10.1016/j.cub.2011.05.016
  17. ↑ Wu L, Ma CA, Zhao Y, Jain A. Aurora B interacts with NIR-p53, leading to p53 phosphorylation in its DNA-binding domain and subsequent functional suppression. J Biol Chem. 2011 Jan 21;286(3):2236-44. doi: 10.1074/jbc.M110.174755. Epub 2010 , Oct 19. PMID:20959462 doi:10.1074/jbc.M110.174755
  18. ↑ Elkins JM, Santaguida S, Musacchio A, Knapp S. Crystal Structure of Human Aurora B in Complex with INCENP and VX-680. J Med Chem. 2012 Sep 13;55(17):7841-8. Epub 2012 Sep 4. PMID:22920039 doi:http://dx.doi.org/10.1021/jm3008954

4af3, resolution 2.75Å

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