2. Academic Validation
  3. CEP192 localises mitotic Aurora-A activity by priming its interaction with TPX2

CEP192 localises mitotic Aurora-A activity by priming its interaction with TPX2

  • EMBO J. 2024 Nov;43(22):5381-5420. doi: 10.1038/s44318-024-00240-z.
James Holder # 1,  Jennifer A Miles # 2 3,  Matthew Batchelor 2 3,  Harrison Popple 1,  Martin Walko 2 4,  Wayland Yeung 5,  Natarajan Kannan 5,  Andrew J Wilson 6,  Richard Bayliss 7 8,  Fanni Gergely 9
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
  • 2 Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
  • 3 School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
  • 4 School of Chemistry, Faculty of Engineering and Physical Sciences, University of Leeds, Leeds, United Kingdom.
  • 5 Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA, USA.
  • 6 School of Chemistry, University of Birmingham, Birmingham, United Kingdom.
  • 7 Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom. r.w.bayliss@leeds.ac.uk.
  • 8 School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom. r.w.bayliss@leeds.ac.uk.
  • 9 Department of Biochemistry, University of Oxford, Oxford, United Kingdom. fanni.gergely@bioch.ox.ac.uk.
  • # Contributed equally.
PMID: 39327527 DOI: 10.1038/s44318-024-00240-z
Abstract

Aurora-A is an essential cell-cycle kinase with critical roles in mitotic entry and spindle dynamics. These functions require binding partners such as CEP192 and TPX2, which modulate both kinase activity and localisation of Aurora-A. Here we investigate the structure and role of the centrosomal Aurora-A:CEP192 complex in the wider molecular network. We find that CEP192 wraps around Aurora-A, occupies the binding sites for mitotic spindle-associated partners, and thus competes with them. Comparison of two different Aurora-A conformations reveals how CEP192 modifies kinase activity through the site used for TPX2-mediated activation. Deleting the Aurora-A-binding interface in CEP192 prevents centrosomal accumulation of Aurora-A, curtails its activation-loop phosphorylation, and reduces spindle-bound TPX2:Aurora-A complexes, resulting in error-prone mitosis. Thus, by supplying the pool of phosphorylated Aurora-A necessary for TPX2 binding, CEP192:Aurora-A complexes regulate spindle function. We propose an evolutionarily conserved spatial hierarchy, which protects genome integrity through fine-tuning and correctly localising Aurora-A activity.

Keywords

Aurora-A; Centrosome; Kinase; Mitosis; Mitotic Spindle.

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