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Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells
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Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells

Published on: July 30, 2020

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Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Mark W Richards1,2, Selena G Burgess1,2, Evon Poon3

  • 1Astbury Centre for Structural and Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|November 13, 2016
PubMed

Insights

Aurora-A kinase stabilizes N-Myc oncoprotein in neuroblastoma. Aurora-A inhibitors disrupt this interaction, offering a new strategy for cancer therapy by targeting N-Myc destabilization.

Area of Science:

  • Oncology
  • Molecular Biology
  • Structural Biology

Background:

  • Myc family proteins are key drivers of oncogenesis, regulating gene expression.
  • N-Myc protein stabilization by Aurora-A kinase is crucial in neuroblastoma development.
  • The ubiquitin-proteasome pathway, involving SCFFbxW7, regulates Myc protein turnover.

Purpose of the Study:

  • To elucidate the structural basis of Aurora-A mediated N-Myc stabilization.
  • To understand how Aurora-A selective inhibitors affect the N-Myc/Aurora-A interaction.
  • To provide a rationale for designing novel neuroblastoma therapeutics.

Main Methods:

  • Co-immunoprecipitation to identify protein interactions.
  • X-ray crystallography to determine the structure of the Aurora-A/N-Myc complex.
  • Biochemical assays to assess ubiquitination and protein stability.

Main Results:

  • Direct interaction identified between Aurora-A catalytic domain and N-Myc region near Myc Box I.
  • Crystal structure of Aurora-A/N-Myc complex determined at 1.72-Å resolution.
  • Aurora-A inhibitors (alisertib, CD532) induce a conformation incompatible with N-Myc binding.

Conclusions:

  • Aurora-A inhibition destabilizes N-Myc, explaining therapeutic efficacy in neuroblastoma.
  • Structural insights enable rational design of cancer therapeutics targeting the Aurora-A/N-Myc complex.
  • Proposed model suggests Aurora-A binding interferes with SCFFbxW7-mediated ubiquitination, preventing N-Myc degradation.
Keywords:
Aurora-A kinaseMycneuroblastomaprotein–protein interactionstructural biology

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