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

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Date
2016-11-11
ICR Author
Chesler, Louis
Poon, Evon
Author
Richards, MW
Burgess, SG
Poon, E
Carstensen, A
Eilers, M
Chesler, L
Bayliss, R
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Type
Journal Article
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Abstract
Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turnover by the ubiquitin-proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by the E3 ubiquitin ligase SCF FbxW7 However, N-Myc protein (the product of the MYCN oncogene) is stabilized in neuroblastoma by the protein kinase Aurora-A in a manner that is sensitive to certain Aurora-A-selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCF FbxW7 We determined the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72-Å resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with the binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCF FbxW7 to disfavor the generation of Lys48-linked polyubiquitin chains.
URI
https://repository.icr.ac.uk/handle/internal/498
DOI
https://doi.org/10.1073/pnas.1610626113
Collections
  • Cancer Therapeutics
  • Clinical Studies
  • Molecular Pathology
Subject
Humans
Neoplasms
Phenylurea Compounds
Azepines
Pyrimidines
SKP Cullin F-Box Protein Ligases
Polyubiquitin
Protein Kinase Inhibitors
Crystallography, X-Ray
Binding Sites
Catalytic Domain
Protein Binding
Phosphorylation
Aurora Kinase A
N-Myc Proto-Oncogene Protein
Research team
Paediatric Solid Tumour Biology and Therapeutics
Language
eng
Date accepted
2016-11-29
License start date
2016-11-11
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (48), pp. 13726 - 13731

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