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Nat Commun DOI:10.1038/s41467-019-11085-0

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

Publication TypeJournal Article
Year of Publication2019
AuthorsAzeez, KRAbdul, Chatterjee, S, Yu, C, Golub, TR, Sobott, F, Elkins, JM
JournalNat Commun
Volume10
Issue1
Pages3166
Date Published2019 Jul 18
ISSN2041-1723
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.

DOI10.1038/s41467-019-11085-0
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31320618?dopt=Abstract

Alternate JournalNat Commun
PubMed ID31320618
PubMed Central IDPMC6639382
Grant List106169/ZZ14/Z / / Wellcome Trust (Wellcome) /