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