Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors.
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ICR Authors
Authors
Richards, MW
Burgess, SG
Poon, E
Carstensen, A
Eilers, M
Chesler, L
Bayliss, R
Burgess, SG
Poon, E
Carstensen, A
Eilers, M
Chesler, L
Bayliss, R
Document Type
Journal Article
Date
2016-11-29
Date Accepted
2016-11-29
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 SCFFbxW7 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 SCFFbxW7 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 SCFFbxW7 to disfavor the generation of Lys48-linked polyubiquitin chains.
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (48), pp. 13726 - 13731
Rights
Source Title
Publisher
NATL ACAD SCIENCES
ISSN
0027-8424
eISSN
1091-6490
Research Team
Paediatric Solid Tumour Biology and Therapeutics