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Structural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP

Author

Listed:
  • Kamal R. Abdul Azeez

    (University of Oxford)

  • Sneha Chatterjee

    (University of Antwerp)

  • Channing Yu

    (Broad Institute
    Dana-Farber Cancer Institute)

  • Todd R. Golub

    (Broad Institute
    Dana-Farber Cancer Institute)

  • Frank Sobott

    (University of Antwerp
    University of Leeds
    University of Leeds)

  • Jonathan M. Elkins

    (University of Oxford
    Universidade Estadual de Campinas, Cidade Universitária Zeferino Vaz, Av. Dr. André Tosello)

Abstract

Aurora kinases B and C (AURKB/AURKC) are activated by binding to the C-terminal domain of INCENP. Full activation requires phosphorylation of two serine residues of INCENP that are conserved through evolution, although the mechanism of this activation has not been explained. Here we present crystal structures of the fully active complex of AURKC bound to INCENP, consisting of phosphorylated, activated, AURKC and INCENP phosphorylated on its TSS motif, revealing the structural and biochemical mechanism of synergistic activation of AURKC:INCENP. The structures show that TSS motif phosphorylation stabilises the kinase activation loop of AURKC. The TSS motif phosphorylations alter the substrate-binding surface consistent with a mechanism of altered kinase substrate selectivity and stabilisation of the protein complex against unfolding. We also analyse the binding of the most specific available AURKB inhibitor, BRD-7880, and demonstrate that the well-known Aurora kinase inhibitor VX-680 disrupts binding of the phosphorylated INCENP TSS motif.

Suggested Citation

  • Kamal R. Abdul Azeez & Sneha Chatterjee & Channing Yu & Todd R. Golub & Frank Sobott & Jonathan M. Elkins, 2019. "Structural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11085-0
    DOI: 10.1038/s41467-019-11085-0
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