title: Two TPX2-dependent switches control the activity of Aurora A.
abstract: Aurora A is an important oncogenic kinase for mitotic spindle assembly and a potentially attractive target for human cancers. Its activation could be regulated by ATP cycle and its activator TPX2. To understand the activation mechanism of Aurora A, a series of 20 ns molecular dynamics (MD) simulations were performed on both the wild-type kinase and its mutants. Analyzing the three dynamic trajectories (Aurora A-ATP, Aurora A-ADP, and Aurora A-ADP-TPX2) at the residue level, for the first time we find two TPX2-dependent switches, i.e., switch-1 (Lys-143) and switch-2 (Arg-180), which are tightly associated with Aurora A activation. In the absence of TPX2, Lys-143 exhibits a "closed" state, and becomes hydrogen-bonded to ADP. Once TPX2 binding occurs, switch-1 is forced to "open" the binding site, thus pulling ADP away from Aurora A. Without facilitation of TPX2, switch-2 exits in an "open" conformation which accompanies the outward-flipping movement of P·Thr288 (in an inactive conformation), leading to the crucial phosphothreonine exposed and accessible for deactivation. However, with the binding of TPX2, switch-2 is forced to undergo a "closed" movement, thus capturing P·Thr288 into a buried position and locking its active conformation. Analysis of two Aurora A (K143A and R180A) mutants for the two switches further verifies their functionality and reliability in controlling Aurora activity. Our systems therefore suggest two switches determining Aurora A activation, which are important for the development of aurora kinase inhibitors.
authors.affiliation: Center of Bioinformatics, Northwest A&F University, Yangling, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Xu
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Xiao
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D064127:Aurora Kinases; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C122167:TPX2 protein, human; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases