title: Two newly identified sites in the N-terminal regulatory domain of Aurora-A are essential for auto-inhibition.
abstract: Aurora-A, a centrosome-localized serine/threonine kinase, is over-expressed in multiple human cancers. We previously reported Zhang et al. (Biochem Biophys Res Commun 2007, 357:347-352) intramolecular inhibitory regulation of Aurora-A between its N-terminal (Nt) regulatory domain (amino acids 1-128, Nt) and C-terminal catalytic domain (aa 129-403, Cd). Here, we identified two essential sites located on the Nt of Aurora-A (Lys 99 and Lys 119) and demonstrate that mutation of either residue to Gly could cause the Nt and C-terminal lobes of the catalytic domain in Aurora-A to form a closed conformation, resulting in a loss of kinase activity. This inactive conformation was reversed by adding C26 peptide (274-299) or Ajuba, which is a required activator of Aurora-A. Over-expression of either mutant induced G2/M arrest. These results provide a basis for future anti-cancer studies targeting Aurora-A.
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai, People's Republic of China, mrbai.fudan@gmail.com.
authors.forename: Meirong
authors.initials: M
authors.lastname: Bai
authors.forename: Jun
authors.initials: J
authors.lastname: Ni
authors.forename: Sunqin
authors.initials: S
authors.lastname: Shen
authors.forename: Jiaxue
authors.initials: J
authors.lastname: Wu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.forename: Yichen
authors.initials: Y
authors.lastname: Le
authors.forename: Long
authors.initials: L
authors.lastname: Yu
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D059447:Cell Cycle Checkpoints; D004789:Enzyme Activation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D060588:LIM Domain Proteins; D050505:Mutant Proteins; D010455:Peptides; D064096:Aurora Kinase A