Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors.
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 SCFFbxW7However, 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 SCFFbxW7We 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 SCFFbxW7to disfavor the generation of Lys48-linked polyubiquitin chains.
Astbury Centre for Structural and Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.|Cancer Research UK Leeds Centre, University of Leeds, Leeds LS2 9JT, United Kingdom.
Mark W
MW
Richards
Astbury Centre for Structural and Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.|Cancer Research UK Leeds Centre, University of Leeds, Leeds LS2 9JT, United Kingdom.
Selena G
SG
Burgess
Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, The Royal Marsden National Health Service Trust, Belmont, Sutton, Surrey SM2 5NG, United Kingdom.
Evon
E
Poon
Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, 97074 Würzburg, Germany.|Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
Anne
A
Carstensen
Theodor Boveri Institute, University of Würzburg, 97074 Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, 97074 Würzburg, Germany.|Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
Martin
M
Eilers
Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, The Royal Marsden National Health Service Trust, Belmont, Sutton, Surrey SM2 5NG, United Kingdom.
Louis
L
Chesler
Astbury Centre for Structural and Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom; r.w.bayliss@leeds.ac.uk.|Cancer Research UK Leeds Centre, University of Leeds, Leeds LS2 9JT, United Kingdom.|Department of Cancer Studies, University of Leicester, Leicester LE1 9HN, United Kingdom.
Richard
0000-0003-0604-2773
R
Bayliss
D064096:Aurora Kinase A / Q000737:chemistry* / Q000235:genetics; D001381:Azepines / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein / Q000737:chemistry* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D025821:Polyubiquitin / Q000737:chemistry / Q000235:genetics; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry* / Q000235:genetics
D001381:Azepines; C000592902:CD532 compound; C550258:MLN 8237; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D025821:Polyubiquitin; D044843:SKP Cullin F-Box Protein Ligases; D064096:Aurora Kinase A
Aurora-A kinase; Myc; neuroblastoma; protein–protein interaction; structural biology