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

DOI: 10.1073/pnas.1610626113

Authors: Mark W. Richards (University of Leeds) , Selena G. Burgess (University of Leeds) , Evon Poon (The Institute of Cancer Research) , Anne Carstensen (University of Würzburg) , Martin Eilers (University of Würzburg) , Louis Chesler (The Institute of Cancer Research) , Richard Bayliss (University of Leeds; University of Leicester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 113 , PAGES 13726 - 13731

State: Published (Approved)
Published: November 2016
Diamond Proposal Number(s): 8359

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.

Journal Keywords: structural biology; Aurora-A kinase; protein–protein interaction; Myc; neuroblastoma

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Documents:
13726.full.pdf