Back to Search
Start Over
Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America . 11/29/2016, Vol. 113 Issue 48, p13726-13731. 6p. - Publication Year :
- 2016
-
Abstract
- Myc family proteins promote cancer by inducingwidespread 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 113
- Issue :
- 48
- Database :
- Academic Search Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 119933079
- Full Text :
- https://doi.org/10.1073/pnas.1610626113