TPX2 promotes AURKA autophosphorylation

TPX2 promotes aurora kinase A (AURKA) activation via autophosphorylation of AURKA on threonine residue T288. Continuous association of TPX2 with AURKA facilitates active state conformation of AURKA and may prevent inactivation of AURKA by protein phosphatases (Bayliss et al. 2003).<p>Molecular dynamic simulations suggest the existence of two TPX2-dependent switches for Aurora A activation. 1) TPX2 binding to Aurora A forces lysine residue K143 of AURKA into an “open” state, which pulls ADP out of the ATP binding site in AURKA to promote kinase activation. 2) Arginine residue R180 of AURKA undergoes a “closed” movement upon TPX2 binding, thus capturing phosphorylated threonine T288 of AURKA into a buried position and locking AURKA in its active conformation. The existence of two TPX2-dependent switches in AURKA activation was further verified by the analysis of two AURKA mutants (K143A and R180A) (Xu et al. 2011).AURKA activation is enabled through phosphorylation and TPX2 binding; these two activating switches act synergistically and withough a predefined order (Dodson and Bayliss 2012).

TPX2通过AURKA（ Aurora kinase A）苏氨酸残基T288的自身磷酸化促进其激活。TPX2与AURKA的持续结合促进了AURKA活性状态的构象，并可能防止蛋白磷酸酶（Bayliss等，2003年）使AURKA失活。分子动力学模拟表明，存在两个TPX2依赖性的Aurora A激活开关。1) TPX2与Aurora A结合迫使AURKA的赖氨酸残基K143进入“开放”状态，从而将ADP从AURKA的ATP结合位点拉出，促进激酶的激活。2) 在TPX2结合后，AURKA的精氨酸残基R180发生“关闭”运动，从而将AURKA的磷酸化苏氨酸T288捕获至隐蔽位置，并锁定AURKA在其活性构象中。通过分析两个AURKA突变体（K143A和R180A），进一步验证了在AURKA激活中存在两个TPX2依赖性的开关（Xu等，2011年）。AURKA的激活是通过磷酸化和TPX2结合实现的；这两个激活开关协同作用，且无预定的激活顺序（Dodson和Bayliss，2012年）。